WO2009128521A1 - Cysteine protease inhibitor - Google Patents

Abstract

Disclosed are: a compound having an excellent inhibitory activity on cysteine protease; and a pharmaceutical agent for the treatment or prevention of a disease selected from the group consisting of osteoporosis, osteoarthrosis deformans, rheumatoid arthritis, Paget disease of bone, hypercalcemia, bone metastasis of cancer and bone pain. Specifically disclosed are: a compound represented by formula (1) or a pharmaceutically acceptable salt thereof; and a pharmaceutical agent or a pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt as an active ingredient.

Description

 Description Title of Invention

Cysteine protease inhibitor Technical Field

 The present invention relates to a novel compound having a cysteine protease inhibitory activity (particularly cathebsin K inhibitory activity), a method for producing the same, and a cysteine protease inhibitor (particularly a cathebsin κ inhibitor) containing the compound as an active ingredient. . In particular, the present invention relates to compounds useful for the treatment or prevention of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, or bone pain. Background art

 In recent years, with the rapid progress toward an aging society, the number of bedridden elderly people has been steadily increasing, which has become a major social and economic problem. Major causes of bedriddenness include stroke, senescence, and fractures due to osteoporosis. It has been pointed out that fractures in the elderly, in particular, often take a long time to heal, so that there is a high possibility that the physical strength will be significantly reduced during treatment and that people will be bedridden. Therefore, prevention, Z or treatment of this is an important issue in maintaining and improving the quality of life of the elderly.

The pathology of osteoporosis is characterized by a decrease in bone strength and an increased risk of fractures due to a decrease in bone mass and changes in the fine structure of bone tissue. In vivo, bone tissue is constantly remodeled by the interaction between bone formation by mesenchymal osteoblasts and bone resorption by hematopoietic osteoclasts, and this balance maintains bone mass. Has been. However, this balance is broken for some reason, and osteoporosis is thought to be caused by the long-lasting state in which bone resorption exceeds bone formation. Since increased bone resorption is closely related to the onset and progression of pathological conditions, it is common to use bone resorption inhibitors in drug therapy for osteoporosis. However, currently used calcinine preparations, estrogen preparations, vitamin K preparations, bisphosphonate preparations and other drugs with bone resorption inhibiting action have problems such as therapeutic effects, immediate effects, side effects, and compliance. Therefore, the development of a bone resorption inhibitor that can be a more effective osteoporosis treatment or prevention drug is desired. Yes.

 Osteoclasts, which are multinucleated giant cells derived from hematopoietic stem cells, play a role in bone resorption. Osteoclasts differentiate from monocyte / macrophage lineage cells into osteoclast progenitors by the action of various cytokines. The progenitor cells then become mononuclear pre-osteoclasts that are attracted to the bone surface and become colonized, multinucleated and become osteoclasts. When activated, osteoclasts surround the bone surface with a wavy rim composed of complex cytoplasmic processes, dissolve hydroxyapatite by releasing acid, and secrete various proteases to form type I collagen. Decompose the protein matrix such as. Since approximately 95% of the bone's organic matrix is collagen, proteases involved in its degradation are considered essential components of bone turnover and the development and progression of osteoporosis. The major protease involved in osteoclast matrix degradation is the cysteine protease, and among them, the involvement of the cathepsin family belonging to the Papain 1 family is widely known. In particular, cathebucin K is attracting attention because it has been reported to be associated with various pathological conditions.

 Cathebsin K, also called cathebsin 0, cathebsin O 2 and cathebsin X, is one of the enzymes of the cystine cathebsin family that is part of the papain par family of systemin proteases. The members of the cathebsin family that are classified as cysteine proteases include: cathebsin B, cathebsin (:, cathebsin F, cathebsin H, cathebsin L, cathebsin 0, cathebsin S, cathebsin V (also called L 2) ), Cathebsin W and cathepsin Z (also called cathepsin X) are known elsewhere, and cathebsin K has a high level of expression in normal osteoclasts and is the main cysteine protease in these cells. (Non-Patent Documents 1 to 3) Cathebsin K is also involved in the function of osteoclasts due to mutations in the cathepsin K gene in dwarfism patients who are thought to be caused by abnormal bone resorption. (Non-patent Document 4) Therefore, by selectively inhibiting cathebsin K, osteoporosis, etc. It is expected to be effective treatment for diseases caused by excessive bone resorption In fact, some clinical trials have been conducted on drugs that selectively inhibit cathebucin K, and therapeutic effects can be obtained. (Non-Patent Documents 5 and 6).

Selective inhibition of cathebsin K may be useful in treating other diseases. Such diseases include autoimmune diseases (eg, rheumatoid arthritis), osteoarthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, or bone pain. For example, cathebsin K is expressed in the synovial membrane and synovial bone destruction sites of patients with rheumatoid arthritis (Non-Patent Documents 7 to 9) and is blocked in disease model animals. Hazardous substances show medicinal properties (Non-patent Documents 10 and 11). The expression level of cathebsin K is elevated in the synovium and cartilage surface layer of osteoarthritis (Non-patent Documents 12 to 14). Cathebsin K expression has been observed in various cancer cells (Non-patent Documents 15 to 19), and its relationship with bone metastasis has been shown (Non-patent Documents 20 and 21). Selective inhibition of cathebsin K may also be useful in treating diseases that develop due to increased osteoclastic bone resorption activity, such as Paget's disease of bone, hypercalcemia, or bone pain. Based on the above, Cathebsin K has attracted attention as a target molecule for the treatment and prevention of diseases, and research and development of cathebsin K inhibitors has been actively conducted. So far, as catebucin K inhibitors, for example, chain ketone type inhibitors (Non-patent document 22), cyclic ketone type inhibitors (Non-patent documents 23 to 26), aldehyde-type inhibitors (Non-patent document 27) ), Α-ketoamide type inhibitors (Non-patent document 28), Ν-arylethylenediamine type inhibitors (Patent documents 1 to 3, Non-patent documents 29, 30, and 34), cyanomethylene type inhibitors ( Patent Literature 4, Non-Patent Literature 3 1 to 33) have been reported.

 As described above, compounds that inhibit cathebucin シ ン have attracted attention as bone resorption inhibitors, and many derivatives have been reported, but they have not yet been put into practical use as therapeutic agents for metabolic bone diseases. In addition, these compounds differ in structure from the compounds of the present invention. It is to be noted that the ァ -arylethylenediamine compound has also been reported as a cathebsin S inhibitor (Patent Document 5).

In particular, Patent Document 1 describes a compound represented by the following general formula (Α) as a low molecular weight compound that inhibits cathebsin Κ.

 Formula (A) However, Patent Document 1 describes only a compound represented by the following formula (B) as a specific compound.

Formula (B) Patent Document 1: Pamphlet of International Publication No. WO02 / 070517 Patent Document 2: Japanese Patent Laid-Open No. 2004-256525 Patent Document 3: International Publication No. WO00 / 048993 Pamphlet Patent Document 4: International Publication No. WO03 / 075836 Pamphlet Patent Document 5: International Publication No. WO04 112709 Pamphlet Non-Patent Document 1 : J. Biol. Chem., 269, 1106 (1994)

Non-patent document 2: Biochem. Biophys. Res. Co. un., 206, p. 89 (1995) Non-patent document 3: FEBS Lett., P. 357, p. 129 U995)

Non-Patent Document 4: Science, 273 (1997), p. 1236

Non-Patent Document 5: 28 ^th ASBMR, Abstl085

Non-Patent Document 6: 29 ^tb ASBMR, Abstll28

Non-Patent Document 7: J. Rheumatol., 25, 1887 (1998)

Non-Patent Document 8: Am J Pathol., 159, 2167 (2001)

Non-Patent Document 9: Arthritis Res Ther., 7, R65-70 (2005)-Non-Patent Document 10: J. Bone Miner. Res., 12, 1396 (1997)

Non-Patent Document 11: Science., 319, 624 (2008)

Non-Patent Document 12: Arthritis Rheum., 42, 1588 (1999)

(Non-Patent Document 13: Arthritis Rheum., 46, 663 pages)

Non-Patent Document 14: Arthritis Rheum., 46, 953 (2002)

Non-Patent Document 15: Cancer Res., 57, 5386 (1997)

Non-Patent Document 16: Maix Biol., 19, 717 (2001)

Non-Patent Document 17: Pancreas., 25, 317 (2002)

Non-Patent Document 18: I Bone Miner Res., 18, 222 (2003)

Non-Patent Document 19: Am J Clin Pathol., 125, p. 847 (2006)

Non-Patent Document 20: Clin Cancer Res., 9, 295 (2003)

Non-Patent Document 21: Mol Carcinog., 47, 66 (2008)

Non-Patent Document 22: J. Am. Chem. Soc., 1998, 120, 9114-9115 Non-Patent Document 23: J. Med. Chem., 1998, 41, 3563-3567

Non-Patent Document 24: J. Med. Chem., 2001, 44, 1380-1395

Non-Patent Document 25: Bioorg. Med. Chem., 2004, 12, 5689-5710 Non-Patent Document 26: J. Med. Chem., 2006, 49, 1597-1612.

 Non-Patent Document 27: Bioorg. Med. Chem. Let ters., 2004, 14, 275-278

 Non-Patent Document 2 8: Bioorg. Med. Chem. Letters., 2005, 15, 3540-3546

 Non-Patent Document 29: J. Med. Chem., 2002, 45, 2352-2354

 Non-Patent Document 30: Bioorg. Med. -6806

 Non-patent document 31: J. Med. Chem., 2003, 46, 3709-3727

 Non-Patent Document 3 2: Bioorg. Med. Chem. Let t., 2004, 14, 4291-4295

 Non Patent Literature 3 3: J. Med. Chem., 2006, 49, 1066-1079

 Non-Patent Document 3 4: Bioorg. Med. Chem. Let t., 2004, 14, 87-90 Disclosure of Invention

Problems to be solved by the invention o o

 The problem to be solved by the present invention is to provide a compound having an excellent cysteine protease inhibitory action.

 Another object of the present invention is to treat or prevent a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, bone paedet disease, hypercalcemia, bone metastasis of cancer, and bone pain. To provide useful compounds. Means for solving the problem

 As a result of intensive studies on compounds having a cysteine protease inhibitory effect, the inventors have found that the following formula (1)

 Formula (1)

The compound having a structure in which a methylene group substituted with a trifluoromethyl group is introduced as a chemical structural feature and a salt thereof have a particularly excellent cysteine protease inhibitory action. Based on these findings, the present invention was completed.

That is, the present invention relates to the following. A compound represented by formula (1), or a medically acceptable salt thereof.

 Formula (1)

 [In Equation (1)

Ar ¹ represents 0 ₆ to ^ 0 aryl group or an aromatic heterocyclic group;

R ¹ represents a group selected from Substituent Group 1;

m represents an integer of 0 to 3; the scale ³ and! ^ ⁴ are the same or different and are substituted with 1 to 6 identical or different groups selected from a hydrogen atom or substituent group 3; {Ct Ce alkyl group, ₃ to ₇ cycloalkyl group, C _{4 to} C ₉ (cycloalkyl) alkyl group, phenyl group, aromatic heterocyclic group, C _{7 to} C ₉ phenyl alkyl group, aromatic heterocyclic ring represents Ci～C ₃ alkyl group) that is substituted with a group;

When both R ³ and R ⁴ are C! Ce alkyl groups optionally substituted with 1 to 6 identical or different groups selected from Substituent Group 3, a single bond, -0-, -NR ⁹ -,-S (O) _q -can be bonded to each other to form a ring structure with 3 to 7 members including the carbon atom to which R ³ and R ⁴ are bonded;

When R ³ and R ⁴ are not bonded to each other to form a ring structure, one of R ³ and R ⁴ represents a group that is not a hydrogen atom;

L represents a single bond or-(CR'QR ^{1 1} ) _s- ;

s represents an integer from 1 to 4;

Ar ² represents a Ce d 0 aryl group or an aromatic heterocyclic group;

 r represents 0 or 1;

Ar ³ represents a C ₆ -C _{1 ()} aryl group, or an aromatic heterocyclic group; n represents 0 or 1

R ⁵ represents a group selected from Substituent Group 1;

p is an integer of 0 to 5; the substituent group 1, a hydrogen atom, a halogen atom, Shiano group, a nitro ^{group, - R 6 a, - OR} 6a, - O (CO) R ", - COOR 6a, -CON (R ^6a ) (R ^6b ),-N (R ^6a ) (R ⁶ ,-NR ^6a (CO) R ^{6 b} ,-NR ^6a (CO) N (R ^6b ) (R ⁶ ,-S (O ) ₂ N (R ^6a ) (R ^6b ), -NR ^6a S (O) ₂ R ^6b , -S (0) _q R ^6a , and -S i (R ⁸ ) ₃ ; Represents a group consisting of: C, C ₆ (alkoxy group, alkylthio group, alkylsulfinyl group, and alkylsulfonyl group) optionally substituted with a halogen atom, a hydroxyl group, and a halogen atom;

R ^6a, R ^6b and R ^6c are the same or different, a hydrogen atom, optionally substituted with R ⁷ C! Cs alkyl group, optionally substituted with R ⁷ C ₂ ~C ₆ alkenyl group, optionally substituted with R ⁷ C ₂ ~C ₆ alkynyl group may 〇 ₃ be substituted by R _⁷ ~ (: ⁷ cycloalkyl, heterocyclyl groups may be substituted with R ^7, R ^A phenyl group that may be substituted with ⁷ , an aromatic heterocyclic group that may be substituted with R ⁷ , a Cy C, a ₃ aralkyl group that may be substituted with R ⁷ , or a substituent that is substituted with R ⁷ alkyl group Ci～C ₃ substituted by heterocyclyl groups may, or substituted in an aromatic heterocyclic group optionally substituted by R ⁷ C, represents -C ₃ alkyl group;

In each substituent in Substituent Group 1, R ^ea and R ^6b , R ^{6 a} and R ^6c , or R ^6b and R ^{6c, which} are present in one group, may be substituted with R ⁷ , To a C ₆ alkyl group, a single bond, —0—, —NR ⁹ —, or S (◯). Can be bonded to each other via-to form a ring structure having 3 to 7 members; q represents an integer of 0 to 2;

R ⁷ is a halogen atom, a hydroxyl group, a carboxyl group, a C, -C ₄ alkyl group, a di-,-di-alkoxy group, a C, -C ₄ alkoxycarbonyl group, a C, -C ₄ alkylsulfonyl group, C, -C ₄ Alkyl sulf An ynyl group or a cyano group,

R ⁸ represents a Ci Ce alkyl group that may be substituted with R ⁷ ;

R ⁹ R ^{10. And} R ¹¹ are the same or different and each represents a hydrogen atom or a C, -C ₆ alkyl group optionally substituted by R ⁷ . ]

(2) A compound represented by the formula (1A) or a medically acceptable salt thereof.

 [In Equation (1)

A represents a C ₆ C ₁₀ aryl group or an aromatic heterocyclic group;

R ¹ represents a group selected from Substituent Group 1;

m represents an integer of 0 3; scale ³ and! ¾ ⁴ may be the same or different and may be substituted with a hydrogen atom or 16 identical or different groups selected from substituent group 3 {, ί ^ alkyl group, C ₃ C ₇ cycloalkyl group, C ₄ C ₉ (cycloalkyl) alkyl group, phenyl group, aromatic heterocyclic group, C ₇ C ₉ phenyl alkyl group, aromatic heterocyclic group Represented C! Cg alkyl group}

R ³ and R ⁴ are both case 1 six identical or different optionally Ci Ce alkyl group optionally substituted by a group selected from Substituent Group 3 is a single ^{bond, - 0 - - NR 9 -} - Bonded to each other via S (0) _q -and can form a ring structure of 3 7 including the carbon atom to which R ³ and R ⁴ are bonded;

When R ³ and R ⁴ are not bonded to each other to form a ring structure, one of R ³ and R ⁴ represents a group that is not a hydrogen atom;

Ar ² represents a C ₆ C ₁₀ aryl group or an aromatic heterocyclic group; Ar ³ represents a Ce d ₀ aryl group or an aromatic heterocyclic group; n represents 0 or 1

R ⁵ represents a group selected from Substituent Group 1;

p is an integer of 0 to 5; the substituent group 1, a halogen atom, Shiano group, a nitro ^{group, - R 6a, - OR 6a} , - O (CO) R 6 a, - COOR 6a, - CON ( R ^6a ) (R ^6b ),-N (R ^6a ) (R ⁶ ,-NR ^6a (CO) R ^6b ,-N

R ^{6 a} (CO) N (R ^6b ) (R ^6c ),-S (O) ₂ N (R ^{6 a} ) (R ^6b ),-NR ^6a S (O) ₂ R ^6b ,-S (O) _q The group consisting of R ^6a , and —S i (R ⁸ ) ₃ ; the substituent group 3 may be substituted with a halogen atom, a hydroxyl group, and a halogen atom (an alkoxy group, an alkylthio group, An alkylsulfinyl group, and an alkylsulfonyl group);

R ^{6 a,} R ^6b and R ^{6 c} are the same or different, a hydrogen atom, optionally substituted with R ⁷ C, -C ₆ alkyl group, optionally substituted with R ⁷ C ₂ -C ₆ alkenyl group, optionally substituted with R ⁷ C ₂ -C ₆ alkynyl group, may also be ₃ to be substituted with R ⁷ (: ₇ cycloalkyl group, the optionally substituted with R ⁷ heterocyclyl group, a phenyl group which may be substituted with R ^7, optionally substituted aromatic optionally heterocyclic group R ^7, optionally substituted with R ⁷ (^ ~ (:, ₃ Ararukiru group, R ⁷ represents in the optionally substituted substituted by heterocyclyl group the Ci ^^ Cs alkyl group, or C substituted with also an aromatic heterocyclic group optionally substituted by R ^7, a -C ₃ alkyl group ;

In each substituent in Substituent Group 1, R ^6a and R ^6b , R ^6a and R ^6c , or R ^6b and R ^6C present in one group may be substituted with R ⁷ Ci Ce If an alkyl group, a single bond, -〇 -, - NR ⁹ -, or S (O) _q - ring structure membered 3-7 linked to one another via can be formed; q is 0 Represents an integer of 2;

R ⁷ represents a halogen atom, a hydroxyl group, a carboxyl group, C, -C ₄ alkyl group, C, -C ₄ alkoxy, C, ~ C ₄ alkoxycarbonyl group, C, -C ₄ alkylsulfonyl group, or a C, ~ C ₄ alkyls Represents the Rufiel group,

R ⁸ and R ⁹ are the same or different and represent a Ci Ce alkyl group which may be substituted with R ⁷ . ]

(3) R ³ may be substituted with 1 to 6 fluorine atoms (C, C ₆ alkyl group, C ₃ C ₇ cycloalkyl group, C ₄ C ₉ (cycloalkyl) alkyl group } Represents;

The compound according to (1) or (2), or a medically acceptable salt thereof, wherein R ⁴ represents a hydrogen atom.

(4) R ³ represents an isobutyl group optionally substituted by 1 to 6 fluorine atoms;

The compound according to (1) or (2), or a medically acceptable salt thereof, wherein R ⁴ represents a hydrogen atom.

(5) The compound or a medically acceptable salt thereof according to any one of (1) to (4), wherein Ar ^L represents a ^ to 0 aryl group.

(6) The compound according to any one of (1) to (5), or a medically acceptable salt thereof, wherein m represents an integer of 1 to 3.

(7) The compound according to (6) or a medically acceptable salt thereof, wherein at least one R ¹ represents -OR ^6a or -N (R ^6a ) (R ^6b ).

(8) -Ar ^1- (R ¹ ) _m force A group represented by the formula (2),

Formula (2)

In equation (2)

R ^la represents -〇R ^6a , or -N (R ^6a ) (R ^6b );

R ^lb represents a halogen atom, -R ^6a , -OR ^6a , or -N (R ^6a ) (R ^6b ), or a compound or a medically acceptable salt thereof according to (1) to (3).

(9) -Ar ^1- (R ¹ ) _m force group represented by formula (3)

1 formula (3)

In equation (3),

R ¹ . ^Represents- N (R ^6a ) (R ^6b ),

R ^ld represents a group selected from Substituent Group 1. The compound according to any one of (1) to (4), or a medically acceptable salt thereof.

(10) The compound according to any one of (1) to (9), wherein at least one of the group substituting RR ¹ , R ⁵ , and the group substituting R ⁵ represents -COOH, Or a medically acceptable salt thereof.

(1 1) any one of (1) or (3) to (9), wherein at least one of the group substituting RR ¹ , R ⁵ and R ⁵ represents a cyano group Or a medically acceptable salt thereof.

(12) The compound according to any one of (1) to (4), or a medically acceptable salt thereof, wherein Ar ¹ represents an aromatic heterocyclic group.

(13) The compound according to any one of (1) to (12) or a medically acceptable salt thereof, wherein Ar ² represents a C _{6 to} C ₁₀ aryl group.

(14) The compound according to any one of (1) to (12), or a medically acceptable salt thereof, wherein Ar ² represents an aromatic heterocyclic group.

(15) A pharmaceutical composition comprising the compound according to any one of (1) to (14), or a medically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(16) A cathebsin K inhibitor comprising the compound according to any one of (1) to (14) or a medically acceptable salt thereof as an active ingredient. (1 7) Osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone containing the compound according to any one of (1) to (14) or a medically acceptable salt thereof as an active ingredient A medicament for the treatment or prevention of a disease selected from the group consisting of hypercalcemia, bone metastasis of cancer, and bone pain. The present invention provides a novel compound having an excellent cysteine protease inhibitory action (particularly cathebsin K inhibitory action).

 Furthermore, the present invention provides a treatment or prevention for a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, and bone pain. Provide medicine. BEST MODE FOR CARRYING OUT THE INVENTION

Terms used alone or in combination in the present specification will be described below. Unless otherwise specified, the description of each substituent is common to each site. When any variable (eg R ^6a , R ^6b , R ^6c , R ⁷ , R ^8, etc.) exists in any component (RR ⁵ etc.), the definition is defined in each component being independent. Also, combinations of substituents and variables are only allowed if such a combination results in a chemically stable compound. If the substituent itself is substituted with more than one group, these multiple groups can be on the same or different carbons as long as a stable structure results.

 In the present invention, the term “Ce C, 0 aryl group” means a group formed by leaving one hydrogen atom bonded to a ring of an aromatic hydrocarbon having 6 to 10 carbon atoms. Non-limiting examples include phenyl group, naphthyl group, indenyl group, tetrahydronaphthyl group, indanyl group, and azulenyl group.

In the present invention, the “C ₇ -C, ₃ aralkyl group” means a group formed by substituting an alkyl group having 1 to 3 carbon atoms with one of the above-mentioned 0 _{6 to 0} aryl groups at an arbitrary position. To do. Non-limiting examples include benzyl group, phenethyl group, naphthylmethyl group, and naphthylethyl group.

In the present invention, the “aromatic heterocyclic group” is a 3 to 10-membered monocyclic or bicyclic ring containing 1 to 5 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. A compound having a certain aromaticity Means a ring system. “3- to 10-membered monocyclic or bicyclic aromatic ring system” has 1 to 5 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom. , A monovalent group obtained by removing a hydrogen atom from a 3- to 10-membered monocyclic or bicyclic aromatic heterocyclic ring. In the case of a bicyclic aromatic heterocyclic group, if one ring is an aromatic ring or an aromatic heterocyclic ring, the other ring may be a non-aromatic ring structure. The number of heteroatoms in the aromatic heterocyclic group and the combination thereof are not particularly limited as long as they can constitute a predetermined number of rings and can exist chemically and stably. Examples of such aromatic heterocyclic groups include, but are not limited to, pyridyl group, virazyl group, pyrimidyl group, pyridazinyl group, furyl group, chenyl group, pyrazolyl group, 1,3-dioxanthdanyl. Group, isoxazolyl group, isothiazolyl group, benzofuranyl group, isobenzofuryl group, benzochelyl group, indolyl group, isoindolyl group, chromanyl group, benzothiazolyl group, benzoimidazolyl group, benzoxazolyl group, pyranyl group, imidazolyl group Group, thiazolyl group, triazinyl group, triazolyl group, furazanyl group, thiadiazolyl group, dihydrobenzofuryl group, dihydroisobenzofuryl group, dihydroquinolyl group, dihydric isoquinolyl group, dihydrobenzoxazolyl group, Hydropteridinyl group, benzoxazolyl group, benzoisoxazolyl group, benzodioxazolyl group, quinolyl group, isoquinolyl group, benzotriazolyl group, pteridinyl group, purinyl group, quinoxalinyl group, quinazolinyl group, Examples thereof include a cinnolinyl group and a tetrazolyl group.

In the present invention, the term “heterocyclyl group” means 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom as a heteroatom, and is saturated even if partially unsaturated. Or a monovalent group obtained by removing a hydrogen atom from a 3- to 10-membered monocyclic or bicyclic aliphatic heterocyclic ring. A heterocyclyl group can contain 1 or 2 -C (= 0)-or -C (= S)-in the ring. The number of heteroatoms in the heterocyclyl group and the combination thereof are not particularly limited as long as they can form a predetermined number of rings and can exist chemically stably. Such heterocyclyl groups include, but are not limited to, for example, piperidyl groups, piperidino groups, pyrrolidinyl groups, pyrrolinyl groups, tetrahydrofuryl groups, dihydrovinylyl groups, hexahydroazepinyl groups, piperazinyl groups, quinuclidinyl groups. , Morpholinyl group, morpholino group, thiomorpholinyl group, thiomorpholino group, oxazolinyl group, 1,4-dioxanyl group, pyranyl group, 2-pyrrolidonyl group, 2-piperidonyl group, 2-imidazolidinyl group, or tetrahydro-3 H 2 -pyrazol-3-onyl group and the like can be mentioned. In the present invention, the “octalogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

 In the present invention, the term “., ˜ø ø alkyl group” means a saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms. Non-limiting examples include, for example, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl group Group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, Examples thereof include t-pentyl group and isohexyl group.

In the present invention, the “C ₃ -C ₇ cycloalkyl group” means a cycloalkyl group having 3 to 7 carbon atoms. Non-limiting examples include cyclic alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group.

In the present invention, “c _{4 to} c ₉ (cycloalkyl) alkyl group” means that the “c, to c ₃ alkyl group” is substituted with one “c _{3 to} c ₇ cycloalkyl group” at any position. Means a group. Non-limiting examples include, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclopropylethyl group, cyclobutylethyl group, cyclopentyl group An ethyl group, a cyclohexylethyl group, a cycloheptylethyl group, and the like.

In the present invention, the “c _{7 to} c ₉ phenylalkyl group” means a group in which the “.! ~ Ji; ^ alkyl group” is substituted with one phenyl group at any position, and is not limited thereto. Examples thereof include benzyl group, phenethyl group, and phenylpropyl group.

In the present invention, “c, ˜c ₆ alkoxy group” means a group consisting of the above “c, ˜c ₆ alkyl group” and an oxy group. Non-limiting examples include, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an S-butoxy group, a 2-methylpropoxy group, an n-pentyloxy group, an iso Pentyloxy group, 2-methylbutoxy group, 1-ethylpropoxy group, 2,2-dimethylpropoxy group, n-hexyloxy group, 4-methylpentoxy group, 3 -Methylpentoxy group, 2-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, t-butoxy group and the like.

 In the present invention, “FCi Ce alkylthio group” means a group consisting of the aforementioned rCi Cfi alkyl group ”and a thio group. Non-limiting examples include methylthio group, ethylthio group, and isopropylthio group.

In the present invention.; A ". (^ - (alkylsulfinyl group" means the "C, -C ₆ alkyl group" and consists of a scan Rufieru group group as but are not limited to, for example, Mechirusuru Finiru Group, ethylsulfinyl group, isopropylsulfinyl group, etc. In the present invention, “rCt Ce alkylsulfonyl group” means a group consisting of the above-mentioned rC! Ce alkyl group ”and a sulfonyl group. Examples that are not included include a methylsulfonyl group, an ethylsulfonyl group, and an isopropylsulfonyl group.

In the present invention, “C, ˜ (: ₆ alkoxycarbonyl group” means a group consisting of the above “(:!-^ Ce alkoxy group” and a carbonyl group. For example, methoxycarbonyl is not limited thereto. Group, an ethoxycarbonyl group, an isopropoxycarbonyl group, etc. In the present invention, the “C ₂ -C ₆ alkenyl group” means a straight or branched chain having 2 to 6 carbon atoms having a double bond. Means an aliphatic hydrocarbon group, including, but not limited to, vinyl, aryl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-prop Nyl group, 2-methyl-2-propenyl group, 4-pentenyl group, 5-hexenyl group, 4-methyl-3-pentenyl group and the like.

In the present invention, the “C ₂ -C ₆ alkynyl group” means a straight chain or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms having a double bond, and is not limited thereto. Examples include ethynyl group, propargyl group, 3-methylpropargyl group, petitil group, 2-butyne-1-yl group, pentyl group, and hexynyl group.

In the present invention, “the alkyl group of C, C ₆ which may be substituted with 1 to 6 identical or different groups selected from substituent group 3” means that the rCt Ce alkyl group is any In the position, it may be substituted with “1 to 6 identical or different groups selected from substituent group 3”, and 2 to 6 groups selected from substituent group 3 When replaced, the same, ~. ; Alkyl groups may be substituted with the same group or may be substituted with different groups. In addition, “C ₃ -C ₇ cycloalkyl optionally substituted with 1 to 6 identical or different groups selected from Substituent Group 3”. “Lu group” and the like mean the same.

In the group substituted with R ⁷ such as “Ci to C ₆ alkyl group optionally substituted with R ⁷ ” and “C _{3 to} C ₇ cycloalkyl group optionally substituted with R ⁷ ” in the present invention. The upper limit of the number of substitution of R ⁷ to be substituted is 10 when R ⁷ is a halogen atom, 5 when R ⁷ is a substituent other than a halogen atom, and 0 to 3 R ⁷ Is preferably substituted with. In the above definition, for example, “C” such as “C,” represents a carbon atom, and the number after that represents the number of carbon atoms. For example, “ji-ji” represents a range of 1 to 6 carbon atoms. Of course, in the present invention, if the number of carbons is different, it means the group having the number of carbons. For example, “rCi C alkyl group” means that the alkyl group defined by “(:, to (: ₆ alkyl group”) has 1 to 4 carbon atoms. The present invention relates to a compound represented by the above formula (1) or a medically acceptable salt thereof, in particular, a compound represented by the above formula (1A), or a medically acceptable salt thereof. In the following, constants common to the compound represented by the formula (1) and the compound represented by the formula (1A) will be described together: In the formulas (1) and (1A), Ar 'represents a C ₆ -C ₁₀ Ariru group, or an aromatic heterocyclic group. "Ariru group" Beauty Specific examples of the "aromatic heterocyclic group" is as defined above, have preferred the A r ¹ "Ariru group" or "aromatic heterocyclic group", phenyl group, a pyrazolyl group, Benzofuranyl group, benzocenyl group, indolyl group, benzothiazolyl group, benzoimidazolyl group, benzoxazolyl group, thiazolyl group, dihydrobenzofuranyl group, dihydroisobenzofuranyl group, dihydroquinolyl group, dihydroisoquinolyl group, dihydrobenzoxazolyl Group, dihydropteridinyl group, benzoxazolyl group, benzoisoxazolyl group, benzodioxazolyl group, quinolyl group, isoquinolyl group, benzotriazolyl group, quinoxalinyl group, and quinazolinyl group In particular, in the above formula (1), R ′ is preferably a phenyl group. Represents a group selected from the substituent group 1. Here, the “substituent group 1” is a hydrogen atom, a halogen atom, a cyan group, a nitro group, -R ^6a , -OR ^6a , -O (CO) R ^6a ,-COOR ^{6 a} ,-CON (R ^6a ) (R ^6b ),-N (R ^6a ) (R ^6b ),-NR ^6a (CO) R ^6b ,-NR ^6a (CO) N (R ^6b ) ( ⁶ R,-S (O) ₂ N (R ^6a ) (R ⁶ ,-NR ^6a S (O) ₂ R ^6b ,-S (O) _q R ^6a , and-S i ( R ⁸ ) represents a group consisting of _3. Here, q represents an integer of 0-2.

Also, R ^6a, R ^6b and R ^6c are the same or different, a hydrogen atom, optionally substituted with R ⁷ C i Ce alkyl group, optionally substituted with R ⁷ C ₂ ~C ₆ alkenyl group, optionally substituted with R ⁷ C ₂ ~C ₆ alkynyl group, Ji may be substituted with R ⁷ ₃ ~. ₇ cycloalkyl, heterocyclyl group, a phenyl group which may be substituted with R ^7, an aromatic substituted with R ⁷ heterocyclic group to which may optionally be substituted with R ^7, optionally substituted with R ⁷ is optionally C ₇ to d ₃ Ararukiru group, 〇 substituted by heterocyclyl groups may optionally be substitution by R ^7, ~ (: ₃ alkyl group, or an optionally aromatic optionally substituted with R ⁷ Represents a Ci Cs alkyl group substituted with a heterocyclic group, R ⁸ represents a Ci Ce alkyl group optionally substituted with R ⁷ .

Furthermore, R ⁷ is a halogen atom, a hydroxyl group, a carboxyl group, a C, to C ₄ alkyl group, a C! C alkoxy group,, to. It represents an alkoxycarbonyl group, a CLCA alkylsulfonyl group, (^ -alkyl sulfinyl group, or cyan group).

Further, each substituent in Substituent Group 1 is substituted with R ^{6 a} and R ^6b , R ^{6 a} and R ^{6 c} , or R ^{6 b} and R ⁶ c force R ⁷ present in one group. C! If it is ~ C ₆ alkyl group, a single ^{bond, - 0 -, - NR 9} -, or S (O) _q - can and child bonded to form a ring structure membered 3-7 to each other through a. Here, Q represents an integer of 0 to 2, and R ⁹ may be substituted with a hydrogen atom or R ⁷ C! It represents a ~ C ₆ alkyl group.

The “ring structure having 3 to 7 members” as R ¹ may contain 2 or less heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as atoms forming such a ring structure. Good. Examples of R ¹ that forms such a “ring structure having 3 to 7 members” include, but are not limited to, for example, 1-piperidyl group, 1-pyrrolidinyl group, morpholino group, thiomorpholino group, 1, 1-dioxochi morpholine-4-yl group, 1-piperazinyl group, and the like. In the formula (1A), R ¹ represents a group selected from the substituent group 1. Where "substituent group 1" is halo gen atom, Shiano group, a nitro ^{group, - R 6a, - OR 6a} , - O (CO) R 6 a, - CO_〇_R ^{6a, - C ON (R 6a} ) (R ^6b ),-N (R ^6a ) (R ^6b ),-NR ^6a (CO) R ^6b ,-NR ^6a (CO) N (R ^6b ) (R ^6c ),-S (O) ₂ N (R ^6a ) (R ^6b ), -NR ^6a S (O) ₂ R ^6b , -S (O) _q R ^6a , and -S i (R ⁸ ) ₃ . Here, Q represents an integer of 0-2. Further, R ^{6 a,} R ^6b and R ^6c are the same or different, a hydrogen atom, optionally substituted with R ⁷ C, ~ C ₆ alkyl group, optionally substituted with R ⁷ C ₂ ~ C ₆ alkenyl group, optionally substituted C ₂ even though -C ₆ alkynyl group in R ^7, optionally substituted 〇 _3-7 cycloalkyl group R ^7, the optionally substituted with R ⁷ heterocyclyl group, a phenyl group which may be substituted with R ^7, an aromatic substituted with R ⁷ heterocyclic group, an optionally substituted C ₇ to d ₃ Ararukiru group R ^7, with R ⁷ Represents a C t to C ₃ alkyl group substituted with an optionally substituted heterocyclyl group, or a C, to C ₃ alkyl group substituted with an aromatic heterocyclic group optionally substituted with R ⁷ . R ⁸ represents a C 1, to C ₆ alkyl group which may be substituted with R ⁷ .

Furthermore, R ⁷ represents a halogen atom, a hydroxyl group, a carboxyl group, a Ci C alkyl group, a dialkoxy group, a Ci C alkoxycarbonyl group, a ^ CA alkylsulfonyl group, or a Ci C alkylsulfinyl group.

Further, in each substituent group in the substituent group 1, ^b R ^{6 a} and R ⁶ present in the one group, R ^{6 a} and 1 ^{6 (;} substituted or scale ⁶¹⁵ and at 1 month 1¾ ^7?? tea even Yoi (: ₁ ~ (: ₆ Arukiru Aru case in groups, a single ^{bond, - 0 -, - NR 9} -, or - S (O) _q - Number 3 attached to one another via It can form a ring structure of 7. Here, q represents an integer of 0 to 2, and R ⁹ represents a Ct Ce alkyl group which may be substituted with R ⁷ .

The “ring structure having 3 to 7 members” as R ¹ may contain 2 or less heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as atoms forming such a ring structure. Good. Examples of R ¹ that forms such a “ring structure having 3 to 7 members” include, but are not limited to, for example, 1-piperidyl group, 1-pyrrolidinyl group, morpholino group, thiomorpholino group, 1, 1-dioxochi morpholine-4-yl group, 1-piperazinyl group, and the like. In the above formulas (1) and (1 A), preferable R ¹ includes a halogen atom, —R ^{6 a} , —OR ^{6 a} , and —N (R ^{6 a} ) (R ^6b ). In said formula (1), m represents the integer of 0-3, Preferably the integer of 1-3 is represented. A preferable example of a combination of “Eight!” ¹ , “R ′”, and “m” (one A r ¹ — (R ¹ ) _m ) can be represented by the following structural formula. -61-

Ol / ,. SO / 600Zdf / X3d

Ol..SO / 600Zdf / X3d TZS8Zl / 600Z OAV

One example of a more particularly preferable combination of “Eight!” ¹ , “R ^] J and“ m ”(one Ar ¹ (R ¹ ) _m ) is a group represented by the following formula (2): It is done.

Formula (2)

[In the formula (2), R ^la represents —OR ^6a , or —N (R ^6a ) (R ^6b );

R ^lb represents a halogen atom, -R ^6a , -OR ^6a , or -N (R ^6a ) (R ^6b ). ]

The definitions of R ^{6 a} and R ^6b in R ^la and R ′ ^b are the same as the definitions of R ^6a and R ^6b in the R ¹ group.

Particularly preferred R ^la in the formula (2) includes -N (R ^6a ) (R ^6b ).

Another example of a more particularly preferable combination of “A r '”, “R ′” and “m” (one Ar ¹ — (R ¹ ) _m ) is a group represented by the following formula (3): Can be mentioned.

1 formula (3) [In formula (3), R ¹ . ^Represents- N (R ^6a ) (R ^6b ),

R ^ld represents a group selected from the substituent group 1. ]

The definition of R ^{6 a} and R ^6b in R ^lc are the same as those defined R ^6a and R ^6b of R ¹ groups of the formula (1A). The definition of the group selected from Substituent Group 1 in R ^ld is the same as the definition of the group selected from Substituent Group 1 in Formula (1A).

In the formulas (2) and (3), when R ^la , R ^lb , R ^lc and R ^ld represent -N (R ^6a ) (R ^6b ), R ^6a and R ^6b are each represented by R ⁷ R ^6a and R ^6b may represent the above-mentioned “ring structure of 3 to 7 members” when the alkyl group of C! Ce optionally substituted with is represented. In the above formulas (1) and (1A), R ³ and R ⁴ may be the same or different and may be substituted with 1 to 6 identical or different groups selected from a hydrogen atom or substituent group 3. good {C i~C ₆ alkyl group, c ₃ to c ₇ cycloalkyl group, c ₄ to c ₉ (cycloalkyl) alkyl group, phenyl group, aromatic heterocyclic group, C ₇ ~ C ₉ phenylalkyl group, an aromatic Represents a C 1, to C ₃ alkyl group substituted with a heterocyclic group.

“Substituent group 3” represents a group consisting of a halogen atom, a hydroxyl group, and d to C ₆ (alkoxy group, alkylthio group, alkylsulfinyl group, and alkylsulfonyl group) which may be substituted with a halogen atom. When both R ³ and R ⁴ are C, C ₆ alkyl groups optionally substituted with 1 to 6 identical or different groups selected from Substituent Group 3, a single bond,-0 -,-NR ⁹

By bonding to each other _via- , -S (O) _q-, a ring structure having 3 to 7 members including the carbon atom to which R ³ and R ⁴ are bonded can be formed. Here, q represents an integer of 0-2. R ⁹ represents a case, hydrogen or R ⁷ in the optionally substituted Ci Cg alkyl group of the formula (1), the case of formula (1A), optionally substituted with R ⁷ C i to C ₆ represents an alkyl group.

The “ring structure having 3 to 7 members” formed by R ³ and R ⁴ is a hetero atom of 2 or less selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as the atoms forming such a ring structure. May be included. Examples of such a “ring structure having 3 to 7 members” include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropyran, pyrrolidine, pipette, and the like. Examples include ring structures such as lysine, thiolane, and thiane.

When R ³ and R ⁴ are not bonded to each other to form a ring structure, one of R ³ and R ⁴ represents a group that is not a hydrogen atom. Preferred examples of the combination of R ³ and R ⁴ include groups represented by the following chemical formulas.

As one specific example of a more preferable combination of R ³ and R ⁴ , R ³ may be substituted with 1 to 6 fluorine atoms (C, C ₆ alkyl group, C ₃ C ₇ cyclo An alkyl group, a C _{4 to} C ₉ (cyclic alkyl) alkyl group}, and a combination in which R ⁴ represents a hydrogen atom. In particular, R ³ represents is 1-6 substituents which may be an isobutyl group by a fluorine atom, combination R ⁴ represents a hydrogen atom. In the formula (1), L represents a single bond or-(CR'OR ^{1 1} ) _s- . Where s! Represents any integer of ~ 4. R ^{1 D} and R ¹¹ are the same or different and each represents a hydrogen atom or a C 1, to C ₆ alkyl group which may be substituted with R ⁷ .

Among them, L is preferably a single bond. In the formula (1) and the formula (1 A), Ar ² represents a C ₆ -C _{1 ()} aryl group or an aromatic heterocyclic group. Specific examples of the “aryl group” and the “aromatic heterocyclic group” are as defined above. The preferred “aryl group” or “aromatic heterocyclic group” of Ar ² includes a phenyl group, A naphthyl group, a enyl group, a pyrazolyl group, a benzofuryl group, a benzocheryl group, an indolyl group, a benzothiazolyl group, a benzoimidazolyl group, a benzoxazolyl group, an imidazolyl group, and a thiazolyl group. Of these, a C _{6 to} C _{1 D} aryl group (particularly a phenyl group) or a pyridyl group is preferable. Ar ² is

When it represents an “aromatic heterocyclic group”, it has excellent metabolic stability. In particular, the aromatic heterocyclic ring is particularly excellent when it represents a pyridine ring substituted with a hydroxyl group, that is, a pyridone ring. In the formula (1), r represents 0 or 1, preferably 1. When r represents 0, n described later represents 0. In the formula (1) and the formula (1 A), Ar ³ represents a C _{6 to} C _{1 Q} aryl group or an aromatic heterocyclic group. Specific examples of the “aryl group” and the “aromatic heterocyclic group” are as defined above, but the preferred “aryl group” or “aromatic heterocyclic group” of Ar ³ includes a phenyl group, Examples include pyridyl group, birazinyl group, pyrimidinyl group, pyridazinyl group, furyl group, chenyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, imidazolyl group, and thiazolyl group. In the formula (1) and the formula (1 A), n represents 0 or 1.

When n represents 1, A r ² and A r ³ are each preferably a monocyclic “aryl group” or “aromatic heterocyclic group”. In the formula (1) and the formula (1 A), R ⁵ represents a group selected from the substituent group 1. The definitions of “substituent group 1”, “R ^6a ”, “R ^6b ”, “R ^6c ”, “R ⁷ ”, and “qj” in “R ⁵ ” in the formula (1) and the formula (1A) are as follows: respectively the formulas (1) and (1A) of the "scale ^1", "substituent group 1" in the "R ^{6 a,"} "R ^6b", "R ^6c", "R ^7", and "q" It is synonymous with the definition of Among them, specific examples of preferred R ⁵ include a halogen atom, a cyano group, -R ^6a , -OR ^6a , -COOR ^6a , and -N (R ^6a ) (R ^6b ).

The “ring structure having 3 to 7 members” as R ⁵ may contain 2 or less heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as atoms forming such a ring structure. Good. Examples of R ⁵ forming such a “ring structure having 3 to 7 members” include, but are not limited to, for example, 1 -piperidyl group, 1 -pyrrolidinyl group, morpholino group, thiomorpholino group, 1, 1- Examples include dioxochiomorpholin-4-yl group and 1-piperazinyl group. In the formula (1) and the formula (1A), p represents an integer of 0 to 5, preferably an integer of 0 to 3. In the above formulas (1) and (1 A), at least one of the groups substituting R ¹ and R ¹ , R ⁵ and R ⁵ represents -COOH, a compound or Its medically acceptable salt is Excellent stability and preferable. Similarly, a compound in which at least one of the group substituting RR ¹ , R ⁵ , and R ⁵ represents a cyano group or a medically acceptable salt thereof is also excellent in metabolic stability. Is preferable. Also, preferred combinations of “L”, “Ar ² ”, “Ar ³ ”, “R ⁵ ”, “r”, “n”, “p” ((R ⁵ ) _p- (Ar ³ ) _n − (Ar ² ) As an example of _r -L-), it can be represented by the following structural formula.

Among the compounds represented by the formula (1), the compounds represented by the formula (1 A) are preferable. In the formula (1A), A r A r ² , A r ³ , RR ³ , R ^{4, R 5, R 6 a} , R 6b, R 6c, R 7, R 8, n, m, and as a combination of p was preferably a combination of preferred groups together as described above for each, and particularly preferably A combination of groups is more preferred.

Table 1 lists preferred compounds and their medically acceptable salts (hereinafter referred to as “preferred compounds”) among the compounds represented by the formula (1).

table 1

R ⁴ R ³

vAr ^1- (R ¹ ) _m

Compound Number (R ⁵ ) _p- (Ar3) _n- (Α _Γ -ίΤ¾

36

⁰ , CH ₃

37 Τ B

H ₃ C _P

 38

 B

H ₃ C _P

 40

41

<General synthesis method>

The compounds and intermediates of the present invention can be synthesized, for example, according to any of the synthetic methods as described below. In each formula, Ar Ar K Ar ³ , L, RR ³ , R ⁴ , R ⁵ , m, n, p, and r are as defined in formula (1). In addition, the reagent or solvent as a condition described in the chemical formula is merely an example as described in the text. Each substituent may be protected with an appropriate protecting group as necessary, and may be deprotected at an appropriate stage. When the abbreviations for substituents, reagents, and solvents in the text or in the table are used, they represent the following.

HATU: O-(7-azabenzo-azol-1 -yl)-N, N, N ', N' -tetramethyl uronium hexafluorophosphate

PyBOP: Benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate X-Phos: 2-(Di-tert-Ptylphosphino)-2 ', 4', 6,-Triisopropyl

-1, 1 '-biphenyl

 DMF: N, N-dimethylformamide

 THF: tetrahydrofuran

 P h: phenyl

 TFA: trifluoroacetic acid

1) Synthesis of compounds of formula (7)

 The compound of the formula (7) can be synthesized using, for example, the method described in US Patent No. US 2006030731.

 That is, first, an imine intermediate of the formula (6) is synthesized by reacting the amino derivative of the formula (4) with the ketone derivative of the formula (5). The compound of formula (7) can be synthesized by reacting this imine intermediate of formula (6) with an appropriate reducing agent. For ketone derivatives of formula (5), for example, Te tr ah edr on, 2006, 62, 5092-5098. and Angew. Ch em. Int. Ed., 1998, 37, 6, 820-821. It can be synthesized with reference to.

Formula (6)

Formula (7)

Further, the compound of the formula (7) is disclosed in WO 2003075836 pamphlet, J. Org. Ch em., 2006, 71, 4320-4323., Bioor g. Med. Ch em. t., 2008, 18, 923-928. etc. That is, first, the amine derivative of the formula (8) in which the hydroxyl group is protected with an appropriate protecting group is converted to trifluoro. React with acetaldehyde to synthesize imine intermediate of formula (9). On the other hand, according to a general method, an organolithium reagent of formula (10) or an organometallic reagent such as a Grignard reagent is prepared. By reacting the organometallic reagent of formula (10) with the imine intermediate of formula (9), the intermediate of formula (11) can be synthesized. Subsequently, the compound of formula (7) can be synthesized by removing the hydroxyl-protecting group P and oxidizing it.

R ⁴ R ³ , 0

OProt R ⁴ R ³

 (Prot = Protective group) .OProt

 isT ゝ

 Equation (8) Equation (9)

1) Deprotection

 2) Oxidation

Formula (7)

2) Synthesis of compound of formula (1) from compound of formula (7)

 (Rou t e A)

A compound of formula (7) can be prepared in the presence of a suitable activator of a carboxyl group (eg HATU, PyBOP), in the presence of a suitable base (eg triethylamine, N-ethyl-N, N-diisopropylamine). Alternatively, in the absence, the compound of formula (1) can be reacted with an amine derivative of formula (12) in a suitable organic solvent (eg DMF, THF) at a temperature range from 0 to the temperature at which the solvent is heated to reflux. Can be synthesized. Fine

H ₂ N ^^ Ar R _{1) m} formula ⁽¹²⁾

 (Route A)

Formula ₍₁₎

(Rou t e B)

A compound of formula (7) can be prepared in the presence of a suitable activator of a carboxyl group (eg HATU, PyBOP), in the presence of a suitable base (eg triethylamine, N-ethyl-N, N-diisopropylamine) or In the absence, in an appropriate organic solvent (for example, DMF, THF), the reaction is performed with an appropriately protected amine derivative represented by formula (13) at a temperature range from 0 to the temperature at which the solvent is heated to reflux. The compound of formula (14) can be synthesized by deprotection under suitable deprotection conditions. The compound of formula (14) can be used in the presence or absence of a suitable additive (eg, myristic acid) in the presence or absence of a suitable Cu reagent (eg, copper (II) acetate). In the presence of a base (eg 2,6-lutidine, triethylamine, N-ethyl-N, N-diisopropylamine) in a suitable organic solvent (eg toluene, acetonitrile, DMF, 2-propanol) or a mixture thereof The compound represented by the formula (1) can be synthesized by reacting with a reagent having a leaving group represented by the formula (15) in a solvent within a temperature range from 0 to the temperature at which the solvent is heated to reflux. it can.

NHProt

(R ⁵ ) _p — (Ar¾— (Ar ² )-,

Formula (7)

L-Ar ^1- (R) _m (Route B) (and = esving group) Equation (15)

 Formula (1)

3) Conversion of the compound of formula (1) and the compound of formula (1 1)

 (Rou t e C)

In the compound of the formula (1) or the compound of the formula (1 1), when n or r is 1 and R ⁵ is a bromine atom or an iodine atom, a Suzuki-Miyaura cross-coupling reaction is performed. Compounds of formula (lc) and formula (1 1 c) in which the structure of R ⁵ is converted to W (aryl group or aromatic heterocyclic group) can be synthesized. That is, a compound of formula (1) or a compound of formula (11) is converted into an appropriate Pd catalyst (eg, Pd ₂ (dba) 3) and an appropriate ligand (eg, X-Phos;), or In the presence of a suitable Pd catalyst and ligand complex (eg PdC 1 ₂ (dppf) · CH ₂ C 1 ₂ ), in the presence of a suitable base (eg cesium carbonate, tert-butoxypotassium) WB (OR) 2 (W is an aryl group or aromatic heterocyclic group) in a solvent (for example, DMF, 2-propanol, water) or a mixed solvent thereof at a temperature at which the solvent is heated to reflux. The compound of formula (1 c) or formula (1 1 c) can be synthesized by reacting with a boric acid reagent represented by the formula:

(Rou t e D)

In the compounds or a compound of formula (1 1) of the formula (1), the case R ⁵ is a bromine atom or an iodine atom, the formula obtained by converting the structure of R ⁵ to Shiano group (I d) and formula (lid ) Can be synthesized.

When n or r is 1, the structure of R ⁵ can be converted to a cyan group by performing a Negishi cross-coupling reaction. That is, a compound of the formula (1) or a compound of the formula (1 1) is converted into an appropriate Pd catalyst (for example, Pd ₂ (dba) ₃ ) and an appropriate ligand (for example, X-Phos;), or an appropriate Pd catalyst and ligand complex (eg P d C 1 ₂ (dp pf) · CH ₂ C 1 ₂ ) in the presence of a suitable solvent (eg DMF, THF) A compound of formula (1d) or formula (lid) can be synthesized by reacting with an appropriate metal cyanide reagent (for example, Zn (CN) ₂ ) at the refluxing temperature.

When n = _r = 0 and L is not a single bond, the compound of formula (1) or the compound of formula (1 1) is heated in a suitable solvent (eg DMF, THF) from room temperature. A compound of formula (Id) or (lid) can be synthesized by reacting with an appropriate metal cyanide reagent (eg, KCN) at the refluxing temperature. (R ^ p-iA ^ Jn-iAr ² )-

(Prat = Protective group) r ¹ — (R ¹ ) _m formula

 Y

Formula (11d)

 (Rou t e E)

In the compound of the formula (1) or the compound of the formula (1 1), when R ⁵ is a bromine atom or an iodine atom, the formula in which the structure of R ⁵ is converted to -N (R ^6a ) (R ^6b ) (1 e) and the compound of formula (lie) can be synthesized.

When n or r is 1, the structure of R ⁵ can be converted to -N (R ^6a ) (R ^6b ) by performing a Buchwald-Hartwig cross-coupling reaction. That is, a compound of formula (1) or a compound of formula (11) is converted into an appropriate Pd catalyst (eg, Pd ₂ (dba) ₃ ) and an appropriate ligand (eg, X-Phos), or Pd catalyst and ligand complex (eg PdC l ₂ (dppf) · CH ₂ C 1 ₂ ) in the presence of a suitable base (eg cesium carbonate, tert-butoxypotassium) in a suitable solvent (For example, toluene, DMF) or in a mixed solvent thereof at room temperature to the temperature at which the solvent is heated to reflux, by reacting with the amine represented by (R ^6a ) (R ^6b ) NH, the formula (le) Alternatively, a compound of formula (1 le) can be synthesized.

If n = r = 0 and L is not a single bond, the compound of formula (1) or the compound of formula (1 1) is replaced with a suitable base (eg N-ethyl-N, N diisopropylamine). ) In the presence or absence of () in a suitable solvent (eg DMF, THF) at room temperature to the temperature at which the solvent is heated to reflux with (R ^6a ) (R ^6b ) NH Thus, the compound of the formula (1 e) or the formula (lie) can be synthesized. To

 N H

N'Ar ¹ — ( ^Rl ) m formula ₍₁₎ .Ar ^1- (R ¹ ) _m formula ( _1e)

Y

Formula (11) Formula (11e)

(Rou t e F)

In the compound of the formula (1) or the compound of the formula (1 1), when n or r is 1 and R ⁵ is a bromine atom or an iodine atom, Ranzu cross-coupling reaction is carried out. Compounds of formula (I f) and formula (1 1 f) in which the structure of ⁵ is converted to a 1-alkynyl group can be synthesized. That is, the compound of formula (1) or the compound of formula (1 1) is converted into an appropriate Pd catalyst (eg, Pd ₂ (dba) 3) and an appropriate ligand (eg, X-Phos), or In the presence of P (eg, P d C 1 2 (dppf) · CH ₂ C 1 ₂ ) and in the presence of a suitable Cu catalyst (eg, copper iodide (I), copper bromide (I)) By reacting with 1-alkyne in the presence of a base (eg, triethylamine, jetylamine, piperidine) in a suitable solvent (eg, DMF, THF, triethylamine) at a temperature at which the solvent is heated to reflux, Compound of formula (1 f) or formula (1 1 f)

You can.

R ⁵ = Br, I (Prot = Protective group)

N ' ^{Ar (Rl) m} formula (")

Formula (11f)

(Rou t e G)

In the compound of the formula (1) or the compound of the formula (1 1), when R ⁵ is a bromine atom or an iodine atom, the compound of the formula (lg) and the formula (1 lg) is obtained by performing hydrogen reduction. Can be synthesized wear. That is, the compound of the formula (1) or the compound of the formula (11) is removed from a room temperature in a suitable solvent (for example, methanol, ethanol, tetrahydrofuran) in the presence of a suitable Pd catalyst (for example, Pd / C). The compound of formula (lg) or the compound of formula (1 lg) can be synthesized by reacting with an appropriate hydrogen source (for example, hydrogen gas, ammonium formate, cyclohexene).

H ₂ -source

" ^Pd "

 (Route G)

t = Protective grou 1 ₎

 Formula (1g)

YY 1) Formula (11g)

In addition to the conversion of Routes A to G described above, a conversion reaction known to those skilled in the art can be performed on the compound of the formula (1) of the present invention. For example, when the compound of the formula (1) of the present invention has an easily convertible substituent such as -◦ (CO) R ^6a , -COOR ^6a , a nitro group, etc., Each can be converted by performing a known reaction. That is, for example, - the 0 (CO) R ^6a represents a hydroxyl group, - COOR ^6a is carboxyl group, or a hydroxymethyl group, a nitro group to amino group can be converted, respectively.

When the compound of the formula (1) of the present invention has a carboxyl group, a substituent such as -COOR ^6a and -CON (R ^6a ) (R ^6b ) is obtained by a reaction well known to those skilled in the art. It can be converted to the compound of the formula (1) of the present invention.

When the compound of the formula (1) of the present invention has a hydroxy group, the compound of the present invention having a substituent such as -OR ^6a and -O (CO) R ^{6a is obtained} by a reaction well known to those skilled in the art. It can be converted to the compound of formula (1).

When the compound of the formula (1) of the present invention has an amino group, -N (R ^6a ) (R ^6b ), -NR ^6a (CO) R ^6b ,- It can be converted to a compound of the formula (1) having a substituent such as NR ^6a (CO) N (R ^6b ) (R ^6c ) and —NR ^6a S (O) ₂ R ^6b . When the compound of the formula (1) of the present invention has a cyano group, the compound of the formula (1) of the present invention having a substituent such as a triazolyl group or a tetrazolyl group by a reaction well known to those skilled in the art. Can be converted to The present invention also relates to a medically acceptable salt of the compound represented by the formula (1). Examples of such salts include salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; maleic acid, fumaric acid, citrate, malic acid, tartaric acid, lactic acid, succinic acid, Benzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, salts with organic acids such as acetic acid, trifluoroacetic acid, formic acid; glycine, lysine, arginine, histidine, ornithine, glutamic acid, asparagine Salts with amino acids such as acids; Salts with alkali metals such as sodium, potassium and lithium; Salts with alkaline earth metals such as Lucium and Magnesium; Salts with metals such as aluminum, zinc and iron; Tetramethylammoni Salts with organic onions such as rum and choline; ammonia, propandamine, and pylori Gin, Piperidine, Pyridine, Ethanolamine, N, N-Dimethylethanololamine, 4-Hydroxypiperidine, t-Octylamine, Dibenzylamine, Morpholine, Darcosamine, Phenyldaricylalkyl ester, Ethylenediamine, N-Methyldarcamine, Guanidine , Jetylamine, Triethylamine, Dicyclohexylamine, N, N '-Dibenzylethylenediamine, Black Pro-In, Pro-In, Diethanolamine, N-Benzylphenylamine, Piperazine, Tris ( Hydroxymethyl) and salts with organic bases such as aminomethane.

 The various medically acceptable salts of the compound represented by the formula (1) can be appropriately produced based on ordinary knowledge in this technical field.

The compounds of the present invention also include stereoisomers, racemates, and all possible optically active compounds of the compound represented by formula (1). In addition, the compounds of the invention may give rise to tautomers depending on the combination of each substituent, and such tautomers are also included in the compounds of the present invention. Examples of combinations of substituents that give rise to such tautomers include, but are not limited to, the following structures.

The compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are excellent cysteine prosthesis. It has a thease inhibitory effect and a particularly superior cathebsin K inhibitory effect. Due to its excellent cysteine protease inhibitory action, the compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are useful as cysteine protease inhibitors (especially cathebsin K inhibitors). .

 The compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are osteoporosis, osteoarthritis, rheumatoid arthritis, bone paget, which can be applied clinically as a cathebsin K inhibitor. It can be used as a medicament for the treatment or prevention of diseases selected from the group consisting of diseases, hypertensive rumumemia, bone metastasis of cancer, and bone pain.

 The compound represented by the formula (1) and a medically acceptable salt thereof can be made into a pharmaceutical composition together with a pharmaceutically acceptable carrier and / or diluent. This pharmaceutical composition can be formed into various dosage forms and administered orally or parenterally. Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, or rectal administration.

 The preparation containing one or more of the compounds represented by the formula (1) of the present invention or a medically acceptable salt thereof as an active ingredient is a carrier or excipient usually used for formulation, It is prepared using the additive. The carrier for the preparation may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, Examples include ethylene glycol and other commonly used ones. Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intravenous injections, intramuscular injections, suppositories, parenteral administration such as transdermal. Good.

The compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are used as pharmaceuticals in terms of safety, stability, efficacy, sustained action, physical properties, pharmacokinetics, preservability, manufacturability, etc. It has good properties. The compound represented by the formula (1) of the present invention or a medically acceptable salt thereof varies depending on the type of disease, administration route, patient symptom, age, sex, body weight, etc. The dose can be administered in the range of 0.1 to 100 mg, preferably in the range of 1 to 10 O mg, in one or several divided doses. However, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or a dose exceeding the above range may be required. In the case of intravenous administration, symptom can be divided into 0.1 to 10 O mg, preferably 0.1 to 1 O mg once or several times per day for adults. It is desirable to administer accordingly. Example The present invention will be described below based on specific examples. However, the present invention is not limited to these examples. The compound numbers given to the respective compounds in the following examples correspond to the compound numbers given to the compounds listed as preferred specific examples in Table 1 above.

The structure of the isolated new compound can be analyzed by mass spectrometry using a single quadrupole instrument equipped with ¹ H NMR and Z or an electron spray source, and other suitable analyzes. Confirmed by law.

The chemical shift (δ: ppm) and force pulling constant (J: Hz) of the ¹ H NMR spectrum (40 OMH z, DM SO -d ₆ or CDC 1 ₃ ) measured are shown. As a result of mass spectrometry, M ⁺ + H, that is, a measurement value observed as a value obtained by adding a proton (H +) to a compound molecular mass (M) is shown. The following abbreviations represent the following: s = si ng 1 et, d = doub 1 et, t = trip 1 et, q = qua rtet, brs = broad sing 1 et, m = mu 1 tip 1 et.

[Reference Example 1]

 (2 S)-2-[((IS)-2, 2, 2-Trifluoro-1-{4-[4-(Methylsulfonyl) phenyl] phenyl} ether) amino]-4 -Fluoro-4- Synthesis of methylpentanoic acid (Reference Example Compound 1)

(Reference Example Compound 丄)

 According to the method described in the literature (W02003075836, J. Org. Chem., 2006, 71, 4320-43 23.), it was synthesized using benzyl N- (tert-butoxycarbonyl) -L-aspartate as a starting material. .

¹ H-NMR (400 MHz, CDC 1 ₃ ) δ (p pm): 8.02 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 4.30 (q, J = 7.0 Hz, 1 H), 3.68 (dd, J = 8. 0, 4. lHz, 1H), 3.10 (s, 3H), 2.26-2.10 (m, 1 H). 2. 07-1. 9 0 (m, 1H), 1. 50 (d, J = 8.0 Hz, 3H), 1.44 (d, J = 8.0 Hz, 3H). ESI / MS m / e: 46 2. 0 (M + + H, C ₂ ! H ₂₃ F ₄ NO ₄ S).

[Reference Example 2]

 Synthesis of (2 S)-2-[{(IS)-2, 2, 2-Trifluoro-1-(4-bromophenyl) ethyl} amino]-4 -Fluoro-4-methylpentanoic acid (Reference Example Compound)

 B ioor g. Me d. Ch em. L et t., 2 II008, 18, 8, 923-928. Starting from benzyl N- (tert-butoxycarbonyl) -L-aspartate And synthesized as

-NMR (400MHz, CDC 1 ₃ ) δ (ppm): 7.52 (2H, dt, J = 8.9,

2.1Hz), 7.26 (2H, t, J: = 4.3Hz), 4.18 (1H, q, J = 7.0Hz),

3. 6 5 (1H, dd, J = 7. 8, 4.4 Hz), 2. 1 6 (1H, ddd, J = 23.3, 1 ο. 0, 4.4 Hz), 1.96 ( 1 H,

7, 6. 1 Hz), 1.46 (6H, dd, J = 2.1.7, 9.5 Hz).

ESI / MS m / e: 3 8 7. 2 (M + + H, C, ₄ H, ₆ Br F ₄ N0 ₂ ). [Reference Example 3]

(2-Aminoethyl) (4-Methoxyphenyl) Amine (Synthesis of Reference Example Compound)

(Reference Example Compound

 According to the method described in the literature (J. Org. Ch em., 1 992, 57, 62 57— 626 5.), 4-methoxydiphosphate hydrochloride was synthesized as a starting material, Obtained.

ESI / MS m / e: 1 6 7. 1 (M + + H, C ₉ H, ₄ N ₂ 0). [(2-Aminoethyl) amino] phenoxy} Acetate (Reference Example

. fire.

 Η (Reference Example Compound

Referring to the method described in the literature (B ioo rg. Med. Ch em., 2006, 14, 6789-6806.), Tert-butyl 2- (4-aminophenoxy) acetate and benzyl N- (2- Hydroxyethyl) Synthesized using rubamate as a starting material and obtained as a free form. ESI / MS m / e: 22 5.1 (M + + H, C _{1 2} H ₂ .N ₂ Q ₂ ).

[Reference Example 5]

 -Aminoethyl- (4-morpholine-4-ylphenyl) amine (Synthesis of Reference Example Compound)

(Reference Example Compound

 According to the method described in the literature (B ioo rg. Med. Chem. Lett. 2006, 16, 1502- 1505.), it was synthesized using 4-morpholinoarin as the starting material, and obtained as hydrochloride. It was.

ESI / MS m / e: 222.2 (M + + H, C _{1 2} H _{1 9} N ₃ 0)

[Reference Example 6]

 (2 S)-2-[((1 S)-2, 2, 2-Trifluoro-1-{4-[4- (Methylsulfonyl) phenyl] phenyl} ethyl) amino--N-(2- (Aminoethyl)-4 -Fluoro-4 -Methyl Penanamide (Synthesis of Reference Compound (Rou te B)

(Reference Example Compound (2 S)-2-[((IS)-2, 2, 2-Trifluoro-1-{4-[4-(Methylsulfonyl) phenyl] phenyl} ethyl) amino]-4 -fluoro-4- Methylpentanoic acid (Reference Example Compound V: 23 lmg) was dissolved in N, N-dimethylformamide (5. OmL). To this solution, HATU (19 Omg) and triethylamine (7 OL) were added and stirred under ice cooling. This solution was added to N- (2-aminoethyl) (tert-butoxy) carboxamide (88 mg) under ice-cooling and stirred for 1 hour under ice-cooling. The reaction was stopped by adding saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (2 S)-2-[((1 S)-2, 2, 2-trifluoro-1-{4-[4- (Methylsulfonyl) phenyl] phenyl} amino) -N- {2-[(tert -butoxy) carbonylamino] ethyl} -4-fluoro-4-methylpentanamide (302 mg) was obtained.

 This (2 S)-2-[((1 S)-2, 2, 2-trifluoro-1-{4-[4- (methylsulfonyl) phenyl] phenyl} ethyl) amino]-N-{2 -[(tert -Butoxy) carbonylamino] ethyl}-4-Fluoro-4-methylpentanamide is dissolved in dichloromethane (2.5 mL), hydrogen chloride (625 and 4mo 1 dioxane solution) is added, and room temperature For 30 minutes. The reaction solution was concentrated under reduced pressure to obtain the title compound (Reference Example Compound: 288 mg, hydrochloric acid salt).

 In addition, the obtained title compound (reference compound, hydrochloride) was suspended in ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (Reference Example Compound, free form).

NMR-NMR (40 OMHz, DMSO-d ₆ ) δ (ppm): 8. 04-7. 88 (m, 5H), 7. 76 (d, J = 8.3 Hz, 2H), 7. 54 (d , J = 8. 3Hz, 2H), 4. 3 5 (m, 1 H), 3. 42-3. 35 (m, 1 H), 3. 25 (s, 3H), 2. 92-2. 83 (m, 2H), 2.45 (t, J = 6.3Hz, 2H), 1.93-1.78 (m, 2H) 1. 4 1 (d, J = 1 1.8Hz, 3H ), 1. 3 5 (d, J = 1 1. 8H z, 3H).

ESI / MS m /: 504.1 (M + + H, C ₂₃ H ₂₉ F ₄ N ₃ O ₃ S).

2-Trifluoro-1-{4-[4-(Methylsulfonyl) Phenyl] phenyl) amino]-4 -fluoro- N-{2-[(4-methoxyphenyl) amino] ethyl}-4 -methylpentanamide (4) Synthesis (Ro ute A)

 (2 S)-2-[((IS)-2, 2, 2-Trifluoro-1-{4-[4-(Methylsulfonyl) phenyl] phenyl} ethyl) amino]-4 -fluoro-4- Methylpentanoic acid (Reference Example Compound: 23 mg) was dissolved in N, N-dimethylformamide (500 L). To this solution, HATU (19 mg) and triethylamine (7 L) were added and stirred under ice cooling. This solution was added to (2-aminoethyl) (4-methoxyphenyl) amine (18 mg of Reference Example Compound, hydrochloride) under ice-cooling, and further triethylamine (14 L) was added under ice-cooling. Stir for 1 hour. The reaction was stopped by adding a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give the title compound (4: 27 mg, trifluoroacetate).

 In addition, a part of the obtained title compound (, trifluoroacetate) was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (4, free form).

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (p pm): 8.01 (t, J = 4.9 Hz, 1 H), 7.93 (d, J = 8.3 Hz, 2H), 7. 83 (d, J = 8.3Hz, 2H), 7.65 (d, J = 8.3Hz, 2H), 7.49 (d, J = 8.0Hz, 2H), 6.69 (d, J = 8.3Hz, 2H), 6. 6 1 (brs, 1 H), 4. 34 (q, J = 7.6H z, 1 H), 3.5 9 (s, 3H), 3. 3 5 (t, J = 6.2 Hz, 1 H), 3. 2 1 (s, 3H), 3.00 (q, J = 6.3 Hz, 2H), 2. 89-2. 80 ( m, 2 H), 1. 90-1. 7 5 (m, 2 H) 1. 4 1 (d, J = 1 3.5 Hz, 3H), 1. 35 (d, J = 1 3.5 Hz, 3H).

ESI / MS m / e: 6 1 0. 2 (M + + H, C _3. H ₃₅ F ₄ N ₃ 0 ₄ S). [Example 2]

tert-Butyl 2-{4-[(2-{(2 S)-2-[((IS)-2, 2, 2-Trifluoro-1-{4-[4- (Methylsulfonyl) phenyl] phenyl] Ru} ethyl) amino]-4 -fluoro-4 -methylpentanoylamino} ethyl) amino] phenoxy} Acetate (8) Synthesis (R oute A)

 In the same manner as in Example 1, (2 S)-2-[((1 S)-2, 2, 2-trifluoro-1-{4- [4- (methylsulfonyl) phenyl] phenyl} ethyl) Amino]-4 -Fluoro-4-methylpentanoic acid (Reference Example Compound IV: 43 mg) tert -Butyl 2- {4- [(2-Aminoethyl) amino] Phenoxy} Acetate (Reference Example Compound A: 37 mg) To give the title compound (8: 62 mg, trifluoroacetate).

 A part of the obtained title compound (8, trifluoroacetate) was dissolved in ethyl oxalate and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (_§_, free form).

'H-NMR (400MHz, CDC 1 ₃ ) <5 (p pm): 8.02 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7. 5 1 (d, J = 8.3Hz, 2H), 7.41 (d, J = 8.3Hz, 2H), 7.20 (t, J = 6.1 Hz, 1H), 6.73 ( d, 10.0Hz, 2H), 6.46 (d, 9.9Hz, 2H), 4.41 (s, 2H), 4.18 (d, J = 6.3Hz, 1H), 3 72-3.66 (m, 1 H), 3.57-3.49 (m, 1 H), 3. 3 1-3. 23 (m, 1H), 3. 12 (s, 3H), 3. 10-3. 06 (m, 2H), 2.98 (s, 1 H), 2. 1 7-1. 89 (m, 2H) 1.52-1.42 (m, 15 H).

ESI / MS m / e: 7 1 0.2 (M + + H, C ₃₅ H "F ₄ N ₃ O ₆ S).

[Example 3]

2-{4-[(2-{(2 S)-2-[((1 S)-2, 2, 2-Trifluoro-1-{4- (Methylsulfonyl) phenyl] phenyl} amino)-4 -fluoro-4-methylpentylamino} ethyl) amino] phenoxy} Acetic acid (9) Synthesis (Rou te A)

 tert-Butyl 2-{4-[(2-{(2 S)-2-[((IS)-2, 2, 2-Trifluo Mouth)-1-{4-[4- (Methylsulfonyl) phenyl] Hue Diethyl} ethyl) amino] -4-fluoro-4-methylpentanoylamino} ethyl) phenoxy} acetate (42 mg) was dissolved in dichloromethane (1 OmL). Trifluoroacetic acid (500 ^ L) was added to this solution and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the title compound (9: 29 mg, trifluoroacetate).

ESI / MS m / e: 654.1 (M + + H, C ₃ H ₃₅ F ₄ N ₃ O ₆ S) Example 4

 (2 S)-2-{[(1 S)-1-(4-Bromophenyl)-2, 2, 2-trifluoroethyl] amino}-4 -fluoro-4 -methyl-N-{2-[ (4-Morpholine-4-ylphenyl) amino] ethyl] Synthesis of Penanamide (20) (Ro ute A)

 In the same manner as in Example 1, (2 S)-2-{[(1 S)-1-(4-bromophenyl)-2, 2, 2,-trifluoroethyl] amino}-4 -fluoro-4 -Methylpentanoic acid (Reference Example Compound: 9 O Omg) was reacted with 2-aminoethyl- (4-morpholine-4-ylphenyl) amine (Reference Example Compound: 9 19 mg, hydrochloride) to give the title compound (20: 1.18 g, free form).

Ή-NMR (400 MHz, CDC 1 ₃ ) <5 (p pm): 7. 45-7. 37 (2H, m), 7. 1 7 (2H, t, J = 9.9 Hz), 7. 08 (1 H, t, J = 6.0 Hz), 6. 86 (2H, s), 6. 52 (2H, s), 4. 04 (1 H, s), 3.86 (4H, t, J = 4.6 Hz), 3.66 (1 H, dd, J = 9. 5, 2.2 Hz), 3.51 -3. 45 (1 H, m), 3. 28— 3. 2 1 (1 H, m), 3. 17-2. 86 (7H, m), 2. 12— 1. 86 (2H, m), 1. 52 — 1. 37 (6H, m).

ESI / MS m / e: 590.2 (M + + H, C ₂₆ H ₃₃ B r F ₄ N ₄ O ₂ )

[Example 5]

 (2 S)-2-[((IS)-2, 2, 2-Trifluoro-1-{4-[4-(Methylsulfonyl) phenyl] phenyl} ethyl) amino]-N-{2-[ (5-black mouth (8-pyrazo mouth [1, 5-aj pyrimidine-7 -yl)) amino] ethyl}-4 -fluoro-4-methylpentanamide (50) synthesis (Rou te B)

 (2 S)-2-[((1 S)-2, 2, 2-Trifluoro-1-{4-[4- (Methylsulfonyl) phenyl] phenyl} ethyl) amino]-N-{2- [(tert -Butoxy) carbonylamino] ethyl}-4 -Fluoro-4-methylpentanamide (Reference compound: 29 mg, hydrochloride) and 5, 7 -Dichlorovirazolo [1, 5-a] Pyrimidine (9 mg ) Was dissolved in 2-propanol (0.25 mL). To this solution was added triethylamine (28; LtL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl oxalate and washed with a mixed solution of saturated saline and saturated aqueous sodium bicarbonate (9: 1). The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (50: 1 lm g, free form).

'H-NMR (400 MHz, CDC 1 ₃ ) δ (p pm): 8. 05-7. 9 5 (m, 3H), 7. 72-7. 62 (m, 2 H), 7. 53- 7.45 (m, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.32 (t, J = 6.1 Hz, 1 H), 6.96 (t, J = 5 .1Hz, 1 H), 6.4 0 (d, J = 2.2 Hz, 1H), 5.84 (s, 1H), 4.19 (q, J = 7.1 Hz, 1H), 3.69 (dd, J = 9.8 Hz, J = 3.4 Hz, 1 H), 3. 59-3. 30 (m, 4H), 3. 13 (s, 1 H), 2. 16-1. 88 (m, 2 H), 1. 49 (d, J = 19.5Hz, 3H), 1.43 (d, J = 19.5Hz, 3H).

ESI / MS m / e: 655.1 (M + + H, C ₂₉ H ₃ , C 1 F ₄ N ₆ 0 ₃ S).

[Example 6]

 (2 S)-2-[((IS)-2, 2, 2-Trifluoro-1-{4-[4-(Methylsulfonyl) phenyl] phenyl} ethyl) amino]-4 -Fluoro mouth-4 -Methyl-N- {2-[(4-Methylphenyl) amino] ethyl} Penanamide (54) Synthesis (Rou te B)

4-Methylphenylboric acid (5 mg), copper acetate (II) (lmg), and myristic acid (3 mg) were suspended in toluene (60 iiL), and 2,6-lutidine (4AI L) was added. (2 S)-2-[((1 S)-2, 2, 2-trifluoro-1-{4- [4- (methylsulfonyl) phenyl] phenyl} ethyl) amino] -N-{2-[(tert -Butoxy) carbonylamino] ethyl}-4 -Fluoro-4-methylpentanamide (Reference Example Compound, free form: 15 mg) Acetonitrile solution (60 L) was added. Stir at room temperature for 5 days. The reaction solution was diluted with ethyl acetate and washed with a mixed solution (9: 1) of saturated brine and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to give the title compound (54: 8 mg, trifluoroacetate). ESI / MS m / e: 594.2 (M + + H, C _3. H ₃₅ F ₄ N ₃ 0 ₃ S) ·

[Example 7]

(2 S)-2-{[(1 S)-2, 2, 2-Trifluoro-1-(4— (3-Cenyl) phenyl) ethyl] amino}-4 -fluoro mouth-4 -methyl-N- {2-[(4 -Morpholine-4 -Iruhue Le) Amino] Etyl} Synthesis of Penyu Namide (43) (Rou te

 (2 S)-2-[{(IS)-1-(4-Bromophenyl)-2, 2, 2,-trifluoroethyl) amino]-4 -Fluoro-4 -methyl- N-[2-{(4 -Morpholine-4-ylphenyl) amino} ethyl] pentanamide (20: 25mg), [1,1'-bis (diphenylphosphino) -ferrocene] dichloropalladium (I 1), dichloromethane complex ( 1: 1 Suspension of 1) (7mg) and 3-diphenylpolonic acid (1 lmg) in a mixed solvent of N, N-dimethylformamide (2. OmL) and 2mo 1ZL sodium carbonate aqueous solution (0.4 mL) I let you. This suspension was stirred in a sealed tube at 100 t for 1.5 hours under a nitrogen atmosphere. The reaction solution was returned to room temperature, filtered through Celite, and the Celai was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography. The obtained fraction was diluted with ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (43: 1 Omg, free form).

NMR-NMR (400MHz, CDC 1 ₃ ) <3 (p pm): 7. 52 (2H, d, J = 8.3 Hz), 7. 44- 7. 43 (1 H, m), 7. 41- 7. 39 (1 H, m), 7. 36— 7. 33 (2H, m), 7. 23-7. 20 (1 H, m), 6. 77 (2H, d, J = 8.8 Hz ), 6.47 (2H, d, J = 8.8Hz), 4. 15-4.10 (1H, m), 3.85 (4H, t, J = 4.6Hz), 3.70 ( 1 H, d, J = 9.8 Hz), 3. 54— 3. 46 (1 H, m), 3. 27-3. 20 (1 H, m), 3.11-2. 98 (6H, m), 2.14- 1.89 (2H, m), 1.55- 1.38 (6H, m).

ES I / MS m / e: 593.3 (M + + H, C _3. H ₃₆ F ₄ N ₄ O ₂ S)

[Example 8]

(2 S)-2-{[(IS)-1-(4-Cyanophenyl)-2, 2, 2-Trifluoroethyl] Amino}-4 -Fluoro-4 -Methyl-N-{2-[(4-Morpholine-4 -ylphenyl) amino] ethyl} Penanamide (27) (Rou te D)

 (2 S)-2-[{(IS)-1-(4-Bromophenyl)-2, 2, 2,-trifluoroethyl) amino]-4 -Fluoro-4 -methyl- N-[2-{(4 -Morpholine-4-ylphenyl) amino} ethyl] pentanamide (20:10 Omg). Tris (dibenzylideneacetone) diparadium (0) (78mg), X-Phos (144mg), and zinc cyanide (8 Omg) was suspended in N, N-dimethylformamide (3. OmL). This suspension was stirred in a sealed tube at 130 ° under a nitrogen atmosphere. The reaction solution was allowed to return to room temperature, filtered through Celite, and the celite was washed with ethyl acetate. The filtrate was diluted with water, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography. The obtained title compound (27, trifluoroacetate) was diluted with ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (27: 7 mg, free form).

¹ H-NMR (400 MHz, CDC 1 ₃ ) <5 (p pm): 7. 50 (2H, d, J = 8.3 Hz), 7. 37 (2H, d, J = 8.0 Hz), 6. 97 (1 H, q, J = 5. 9 Hz), 6. 87 (2 H, d, J = 8.5 Hz), 6.5 1 (2H, d, J = 7.8 Hz), 4.1 5—4.09 (1H, m), 3.86 (4H, t, J = 4.6 Hz), 3.70 (1 H, d, J = 8.8 Hz), 3.57 -3.49 ( 1 H, m), 3. 28— 3. 2 1 (1 H, m), 3. 13-2. 96 (6H, m), 2. 12- 1. 88 (2H, m), 1. 54 — 1. 38 (6H, m).

ESI / MS m / e: 536.2 (M ⁺ + H, C ₂₇ H ₃₃ F ₄ N ₅ O ₂ )

[Example 9]

(2 S)-2-[((IS)-2, 2, 2-Trifluoro-1-{4-[(2-Hydroxyethyl) amino] phenyl} ether) amino]-4 -Fluoro-4 -Methyl-N- {2-[(4-morpholine -4-Rufenyl) amino] ethyl} synthesis of penanamide (33) (Rou te

 . (2 S)-2-[{(IS)-1-(4-Bromophenyl)-2, 2, 2,-Trifluoro} amino]-4 -Fluoro-4 -methyl- N-[2-{( 4-morpholine-4-amino) ethyl] pen] namide (20: 60mg), tris (dibenzylideneacetone) diparadium (0) (19mg), X-Phos (17mg), and cesium carbonate (132mg) ) Was suspended in toluene (3. OmL). Ethanolamine (31 “L) was added to the suspension, and the mixture was stirred in a sealed tube under a nitrogen atmosphere at 100 t for 1.5 hours. The reaction solution was returned to room temperature, filtered through celite, and ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give the title compound (33: 1 Omg, trifluoroacetate).

 A part of the title compound (33, trifluoroacetate salt) was dissolved in dimethyl sulfoxide, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (33, free form).

¹ H-NMR (400 MHz, CDC 1 ₃ ) <5 (p pm): 7. 28 (1H, t, J = 5.7 Hz), 7. 02 (2H, t, J = 7.2 Hz), 6. 77 (2H, d, J = 8.8 Hz), 6. 45 (2 H, d, J = 8.8 Hz), 6. 40 (2 H, d, J = 8.5 Hz), 4. 16—4 1 1 (1 H, m), 3. 98-3. 9 1 (1 H, m), 3. 79 (4H, t, J = 4.8 Hz), 3. 70 (2H, t, J = 5. 4Hz), 3.51 (1H, d, J = 8.5Hz), 3.48—3.41 (1H, m), 3. 19-3.00 (6H, m), 2.95 (4H, t, J = 4.6 Hz), 2.75 (1 H, brs), 2.10-1.79 (2H, m), 1.40 (3H, d, J = 19.0Hz), 1.34 (3 H, d, J = 19.3 Hz).

ESI / MS m / e: 570.3 (M + + H, C ₂₈ H ₃₉ F ₄ N ₅ O ₃ ),

[Example 10]

(2 S)-2-({(IS)-1-[4-(3, 3 -Dimethyl-3 -Silabuto-1 -Inyl) Hue Nyl]-2, 2, 2-trifluoroethyl} amino)-4 -fluoro mouth-4 -methyl-N-{2-[(4 -morpholine-4 -ilphenyl) amino] ethyl} pen tanamide (47 ) Synthesis (Ro ute F)

 (2 S)-2-[{(IS)-1-(4-Bromophenyl)-2, 2, 2,-trifluoroethyl} amino]-4 -Fluoro-4 -methyl- N-[2-{ (4-Morpholine-4-ylphenyl) amino} ethyl] Pen Yunamide (20: 70mg), Tris (dibenzylideneacetone) dipalladium (0)

(60 mg), X-Phos (56 mg), and copper (I) iodide (2 mg) were suspended in triethylamine (3. OmL). This suspension was stirred in a sealed tube under a nitrogen atmosphere at 100 t for 1 hour. The reaction solution was returned to room temperature, filtered through celite, and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was roughly purified by thin layer silica gel chromatography (hexane Z ethyl acetate = 1Z3). Further, the obtained crude product was purified by high performance liquid chromatography to obtain the title compound (47: 1 lmg. Trifluoroacetate).

 A part of the title compound (47, trifluoroacetate) was dissolved in ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution. The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (47, free form).

¹ H-NMR (400 MHz, CDC 1 ₃ ) δ (p pm): 7. 42 (1H, d, J = 8.3 Hz), 7. 35 (1H, d, J = 8.3 Hz), 7. 26 (1 H, d, J = 7.8 Hz), 7. 1 7 (1 H, d, J = 8.3 Hz), 7. 08 (1 H, brs), 6. 97 (1 H, d, J = 8.8 H z), 6. 80 (1H, d, J = 9.0 Hz), 6. 56 (1 H, brs), 4. 13— 3. 97 (3H, m), 3. 79 (2H, t, J = 4.9 Hz), 3. 60— 3.52 (2H, m), 3. 40-2. 9 1 (7H, m), 2. 00-1. 82 (2H, m ), 1. 42-1. 32 (6H, m), 0.18 (9H, s).

ESI / MS m / e: 60 7.3 (M + H, C ₃₁ H ₄₂ F ₄ N ₅ 0 ₂ S i) [Example 11]

 (2 S)-2-[((1 S)-2, 2, 2,-trifluoro-1 -phenylethyl) amino]-4-fluor-4 -methyl-N-{2-[(4 -morpholine-4 -Ylphenyl) amino] ethyl} Penanamide (19) Synthesis (R oute G)

 (2 S)-2-{[(IS)-1-(4-Bromophenyl)-2, 2, 2-trifluoroethyl] amino}-4 -fluoro-4 -methyl-N-{2-[( 4-morpholin-4-ylphenyl) amino] ethyl} Penanamide (20: 4 Omg) was dissolved in methanol (2. OmL). To this solution was added palladium-activated carbon (10% Pd) (4 mg), and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction solution was filtered through celite, and the celite was washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with an aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (19: 3 lmg, free form).

¹ H-NMR (400 MHz, CDC 1 ₃ ) δ (p pm): 7. 38— 7. 30 (4H, m), 7. 13 (1H, t, J = 5.5 Hz), 6. 87— 6 79 (2H, m), 6. 50 (2H, d, J = 9.1 Hz), 4. 15-4. 04 (1 H, m), 3.85 (4H, t, J = 4. 6Hz), 3.69 (1H, d, J = 10. OHz), 3.49—3.41 (1 H, m), 3. 27-3. 19 (1 H, m), 3. 09- 3. 00 (6 H, m), 2.11— 1.87 (2H, m), 1.51— 1. 3 8 (6H, m).

ESI / MS m / e: 51 1.2 (M + + H, C _{2 e} H ₃₄ F ₄ N ₄ O ₂ ) Hereinafter, the compounds described in Examples 12 to 16 are the same as those described in Example 1. In this way, synthesis was performed using the corresponding starting materials and reagents. Table 2 below summarizes the structure and the observed M + + H observed by LCZMS, that is, the value observed by adding proton (H +) to the compound molecular mass (M). Table 2

[Example 1 7]

 (2 S)-N-[2- (Pyridine-2-ylamino) ethyl]-4 -methyl-2-{[(1 S)-2, 2, 2-trifluoro-1-(6-methoxypyridine-3 -Yl) Ethyl] Amino} Pen Yunamid (94) Synthesis

Acetic acid (0.2 mL) was added to a DMF solution (2 mL) of tert-butyl N- (2-oxoethyl) strong rubamate (90 mg) and 2-aminopyridine (56 mg), and the mixture was stirred at room temperature for 1 hour. Sodium borohydride (94 mg) was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour. Ethyl acetate and water were added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and methanol (1 mL) and hydrogen chloride (4 mol / L, 1,4-dioxane solution, 1 mL) were added to the residue, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product of N- (2-aminoethyl) -pyridine-2-amine hydrochloride. (2 S)-4 -Methyl-2-{[(1 S)-2, 2, 2-Trifluoro-1-(6-methoxypyridin-3-yl) ethyl] amino } Pentanoic acid (32 mg) was added and dissolved in N, N-dimethylformamide (1 mL). HATU (57 mg) and triedgilamine (70 L) were added to this solution and stirred at 0 t for 1 hour. The reaction was stopped by adding water to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. Concentrate the filtrate under reduced pressure and remove the residue to HP Purification by LC gave the title compound (94:19 mg, trifluoroacetate).

Ή-NMR (400MHz, CDC1 ₃ ) δ: 8.07 (1Η, d, J = 2.4 Hz), 7.85-7.63 (3H, m), 7.49 (1H, brs), 6.84-6.67 (3.3H, m), 3.94 (1H, d, J = 4.6 Hz), 3.85 (3H, s), 3.48—3.44 (2H, m), 3.31—3.26 (3H, m), 1.80-1.78 (1H, m), 1.48-1.47 (2H , m), 0.96—0.90 (6H, m).

ESI / MS m / e: 440.15 (M ++ H, C ₂₁ H ₂₉ F ₃ N ₅ 0 ₂ ) Hereinafter, the compounds described in Examples 18 to 37 are prepared according to the method described in Example 17. Synthesized using the starting materials and reagents. Table 3 summarizes the structure and measured values observed by LCZMS as M ⁺ + H, that is, the value obtained by adding proton (H +) to the compound molecular mass (M).

Table 3

Example No.Compound No.M ++ H

 34 111 483.15

 35 112 483.15

 36 113 497.2

 37 114 439.15

[Example 38]

 For compounds synthesized according to the methods in the above examples or in the same way, high-performance liquid chromatography (HPLC) analysis, and time-of-flight mass spectrometer (TOF-MS) with an electrospray ion source Analysis was also carried out by mass spectrometry using of (F light-Mass Spectroscopy).

 Table 4 below shows the retention time (unit: minute) of the compound in the HPLC analysis under the following analysis conditions as the HPLC retention time.

 The compound numbers shown in Table 4 below correspond to the compound numbers given to the compounds listed as preferred specific examples in Table 1 above.

HPLC measurement conditions

Measuring device: Hew l e t t-P a c k a r d 1 100 HPLC

Column: I m t a k t C a d e n a a CD-C 1 8 1 0 OmmX 4.6 mm 3 m UV: PDA detection (254 nm)

Column temperature: 40 degrees

Gradient conditions:

Solvent: A: H ₂ 0 Bruno acetonitrile = 9 5/5

 0. 05% TFA (trifluoroacetic acid)

B: H ₂ OZ phase 2 = 5Z9 5

 0.0 5% TFA (trifluoroacetic acid)

 Flow rate: 1. OmLZ min

 Gradient: 0 to 1 minute, Solvent B: 10% Solvent A: 90%

1 to 13 minutes, Solvent B: 10% → 70% Solvent A: 90% → 30% 1 3 to 14 minutes, Solvent B: 70% —100% Solvent A: 30% → 0%

 14-16 minutes, Solvent B: 100% Solvent A: 0%

1 6-1 9 min, solvent B: 1 00% → 10% solvent eight: 0% → 90% Further, the results of mass spectrometry, was observed by the apparatus and analytical conditions shown in the "M ⁺ + H" (Obs. Ma ss: the actual value obtained by adding proton (H +) to the molecular mass (M) of the compound) and the calculated value (pre d. Ma ss) of “M + + H” The composition formulas (Formu 1 a) calculated from the value of “M ⁺ + H” are shown in Tables 2A to 2E below.

TOF-MS measurement conditions

Mass spectrometer: Shimadzu LCMS-I T-TOF

L C: P ro m i n e n c e

Column: Phenomene x Synegi HyDro-RP 1 00 A 4.0 mmX 20 mm 2 p, m

UV: PDA detection (2 54 nm)

Flow rate: 0.6mL

Column temperature: 40 degrees

Detection voltage: 1. 60 kV

Gradient conditions:

Solvent: A: H ₂ 0 / acetonitrile = 9 5/5

 0. 0 5% TFA

B: H ₂ OZ-acetonitrile = 5/9 5

 0. 05% TFA

 Flow rate: 0.5mLZ min

 Gradient: 0 to 0.2 minutes, Solvent B: 2% Solvent A: 98%

 0.2 to 2.5 minutes, Solvent B: 2% → 100% Solvent A: 98% → 0%

 2. 5 to 3.8 minutes, Solvent B: 100% Solvent A: 0%

 3. 8 ~ 4.0 min, Solvent B: 1 00% → 2% Solvent 8: 0% → 98%

4.0 ~ 5.0 min, Solvent B: 0% Solvent A: 100% Size

Synthesis method HPLC retention time obs Mass Pred Mass Formula Compound number

(Route) ^{(min) (M + + H) (} M + + H) (M)

 113 A 8.96 497.2375 497.2370 C24H31F3N404

114 A 10.48 439.2325 439.2315 C22H29F3N402

[Example 39]

 Cathebsin K inhibitory activity was measured for compounds synthesized according to the methods of the above Examples or in the same manner. The compound numbers shown in Table 3 below correspond to the compound numbers given to the compounds listed as preferred specific examples in Tables 1A to 1M above.

 Cathebsin K used for the evaluation of inhibitory activity was expressed transiently in animal cells HEK293 T cells (manufactured by Gennhunter), and the cell fraction was collected with a surfactant to obtain an active enzyme.

 Enzyme solution A was prepared at 2.1 times the final concentration with Atsey buffer (5 OmM sodium acetate, 50 mM sodium chloride, 2 mM DTT, ρ 2.5.δ). Test compound solution Β was prepared with dimethyl sulfoxide (DMSO) to a final concentration of 50 times. Substrate solution C is a fluorescent buffer benzyloxycarbonyl-L-leucyl-L-arginyl-4-methyl-coumaryl-7-amide (Z-Leu-Arg-MCA (Peptide Institute)) Prepared to 10 with liquid.

 Test compound solution B (1.6 L) was added to enzyme solution A (38.4 L), mixed, and incubated for 15 minutes at room temperature. Substrate solution C (40 L) was added to this incubation solution and reacted at room temperature for 30 minutes. This enzyme reaction solution was measured at an excitation wavelength of 355 nm and a measurement wavelength of 460 nm, and the enzyme activity was calculated from the fluorescence intensity of the released 7-amino-4-methylcoumarin. The inhibition rate of the test compound was calculated based on the enzyme activity when DMSO was added instead of the test compound solution B as 100%, and the 50% inhibitory concentration against cathepsin K was calculated by fitting the dose response curve.

The results are shown in Table 5. However, the symbols (10, +10, +++) in the table represent the inhibitory activity values as follows. Where p IC ₅ . Is the value that represents the negative logarithm (1 l og,. (IC ₅₀ )) of the IC ₅₀ value at 50% inhibitory concentration.

5. 0≤p IC ₅₀ <7.5, +

7. 5≤p IC ₅₀ <8. 5: + +

8. 5≤p IC ₅₀ : +++ Table δ

[Example 40] A metabolic stability test using human liver microsomes was performed on the compounds synthesized according to the methods of the above Examples and the compound of the formula (B) (compound disclosed in International Publication No. WO 0 2 Z0705 17 pamphlet) The residual rate of each compound was calculated.

 The test compound solution (10 /, I O O M acetonitrile solution) was added to human liver microsome solution (950 / xL) on an ice bath, and this solution was divided into two equal parts. One was solution A and the other was solution B. The composition of the human liver microsome solution is as follows.

20 mg / mL r o t e i n chick liver microsome (Xe n o t c h LLC L nexa, US): 10 L

 50 OmM potassium phosphate buffer (pH7.4): 200 L

1 OmM EDTA solution: I O O L

6 OmM Mg C 1 ₂ solution: 50 L

 10 OmM Glucose mono 6-phosphate solution: 50

 100 1. U./mL glucose-6-phosphate dehydrogenase solution: 10 L

Purified water: Acetonitrile (50 0 j L) was added to 5 30 L solution A (4 80 ML) on an ice bath, followed by 25 mM N ADPH solution (20 / zL). After stirring with vortex, the mixture was centrifuged at 4 for 10 minutes (3 000 rpm), and the supernatant was used as a sample with a reaction time of 0 minutes.

 25 mM NADPH solution (20 L) was added to solution B (480 L), followed by incubation at 37 for 25 minutes. Acetonitrile (500 / xL) was added to stop the reaction, followed by stirring using a vortex. Centrifugation was performed at 4t for 10 minutes (3000 rpm), and the supernatant was used as a sample with a reaction time of 25 minutes.

LCZMS measurement was performed on a sample with a reaction time of 0 minute and a sample with a reaction time of 25 minutes. Based on the peak area of the target molecular weight in this MS measurement, the residual rate of the reaction time 25 minute sample relative to the reaction time 0 minute sample was calculated as 100 minutes. The results are shown in Table 6. Table 6

Industrial applicability

 The compound represented by the above formula (1) of the present invention and a medically acceptable salt thereof have a cysteine protease inhibitory action (particularly cathebsin Κ inhibitory action) and can be applied clinically as a cysteine protease inhibitor. It is used as a medicine for treating or preventing a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, cancer bone metastasis, and bone pain. be able to.

Claims

Claim scope Compound represented by formula (1) or a medically acceptable salt thereof. Formula (1) [In Formula (1), Ar 1 represents (^ to 0 aryl group or an aromatic heterocyclic group; R 1 represents a group selected from Substituent Group 1; m represents 0 to 3 R3 and R4 are the same or different and may be substituted with a hydrogen atom or 1 to 6 identical or different groups selected from substituent group 3 (C, C6 alkyl) Group, 03 to (: 7 cycloalkyl group, C4 to C9 (cycloalkyl) alkyl group, phenyl group, aromatic heterocyclic group, C7 to C9 phenylalkyl group, Ct ^ alkyl group substituted with aromatic heterocyclic group R 3 and R 4 may both be substituted with 1 to 6 identical or different groups selected from Substituent Group 3. In the case of an alkyl group, a single bond,-0-,- NR9-,-S (0) q-are bonded to each other to form a ring structure with 3 to 7 members, including the carbon atom to which R 3 and R 4 are bonded. When R3 and R4 are not bonded to each other to form a ring structure, one of R3 and R4 represents a group that is not a hydrogen atom; L represents a single bond, or-(CR R1 1 s represents an integer of 1 to 4; Ar2 represents. (; to ^ 0 aryl group or an aromatic heterocyclic group; r represents 0 or 1; Ar3 Represents a Cs C, oaryl group, or an aromatic heterocyclic group; n represents 0 or 1; R5 represents a group selected from the substituent group 1; p represents an integer of 0 to 5; Substituent group 1 is a hydrogen atom, a halogen atom, a cyano group, a nitro group, -R6a, -OR6a, -O (CO) R6a, -COOR6a, -CON (R6a) (R6b), -N (R6a) (R6b),-NR6a (CO) R6 b,-NR6a (CO) N (R6b) (R6c),-S (O) 2N (R6 a) (R6b),-NR6aS (O) 2 R6b,-S ( O) qR6a, and -S i (R8) 3; Substituent group 3 includes a halogen atom, a hydroxyl group, and a halogen atom Represents a group consisting of (alkoxy group, alkylthio group, alkylsulfinyl group, and alkylsulfonyl group); and R6a, R6b, and R6C are the same or different and represent a hydrogen atom , R7 may be substituted. , ~. (; Alkyl group, C2-C6 alkenyl group optionally substituted with R7, C2-C6 alkynyl group optionally substituted with R7, C3-C7 cycloalkyl group optionally substituted with R7, R7 A heterocyclyl group optionally substituted with R7, a phenyl group optionally substituted with R7, an aromatic heterocyclic group optionally substituted with R7, a C7 to d3 aralkyl group optionally substituted with R7 A C, -C3 alkyl group substituted with a heterocyclyl group optionally substituted with R7, or a C! -C3 alkyl group substituted with an aromatic heterocyclic group optionally substituted with R7. In each substituent in Substituent Group 1, R6a and R6b, R6a and Rfic, or R6b and R6c, which are present in one group, may be substituted with R7, ~ .alkyl A single bond,-0-,-NR9-, or S (0) q- Can form a ring structure having 3 to 7 members; q represents an integer of 0 to 2; R7 represents a halogen atom, a hydroxyl group, a carboxyl group, a C! CA alkyl group, a C! CA alkoxy group, a C1 ~ C4 represents an alkoxycarbonyl group, C 1, Αalkylsulfonyl group, C 1, -C 4 alkylsulfinyl group, or cyano group, R 8 represents a C, -C 6 alkyl group optionally substituted by R 7; R 9, R 1 Q , And R 11 are the same or different and each represents a hydrogen atom, or a C, -C6 alkyl group optionally substituted with R 7.] Claim 2. Represented by the formula (1A) The compound according to 1, or a medically acceptable salt thereof Formula (1A)

 [In Equation (1)

Ar ¹ . (; Represents ~ 0 0 aryl group or aromatic heterocyclic group;

R ¹ represents a group selected from Substituent Group 1;

m represents an integer of 0 to 3;

R ³ and R ⁴ may be the same or different and each may be substituted with a hydrogen atom or 1 to 6 identical or different groups selected from substituent group 3 (C, ~ (: ₆ alkyl group) , 〇 _3-7 cycloalkyl group, C ₄ -C ₉ (cycloalkyl) alkyl group, phenyl group, aromatic heterocyclic group, C ₇ -C ₉ Fueniruaruki Le group, Ci～ substituted with an aromatic heterocyclic group C ₃ alkyl group}

Both R ³ and R ⁴ may be substituted with 1 to 6 identical or different groups selected from Substituent Group 3. 〇, ~ (: In the case of ₆ alkyl groups, a single bond,-0- ^{, -NR 9 -, - S (} 0) q - bonded to each other via a, can form a ring structure membered 3-7 including the carbon atom to which R ³ and R ⁴ are attached;

When R ³ and R ⁴ are not bonded to each other to form a ring structure, one of R ³ and R ⁴ represents a group that is not a hydrogen atom;

Ar ² represents a C ₆ -C _{1 ()} aryl group, or an aromatic heterocyclic group; Ar ³ represents a Cs doaryl group or an aromatic heterocyclic group;

n represents 0 or 1;

R ⁵ represents a group selected from Substituent Group 1:

p represents an integer of 0-5; substituent group 1, a halogen atom, Shiano group, a nitro ^{group, - R 6a, - OR 6} a, - O (CO) R 6 a, - COOR 6a, - CON (R ^6a ) (R ^6b ),-N (R ^6a ) (R ⁶ ,-NR ^6a (CO) R ^6b ,-NR ^{6 a} (CO) N (R ^6b ) (R ⁶ ,-S (O) ₂ N (R ^{6 a} ) (R ^6b ), -NR ^6a S (O) ₂ R ^6b , -S (O) _q R ^6a , and -S i (R ⁸ ) ₃ ; , A halogen atom, a hydroxyl group, and ^ ~ (^ (alkoxy group, alkylthio group, alkylsulfinyl group, and alkylsulfonyl group) optionally substituted with a halogen atom;

R ^{6 a,} R ^6b and R ^{6 c} are the same or different, a hydrogen atom, an Ci Ce alkyl group optionally substituted by R ^7, optionally substituted with R ⁷ C ₂ ~C ₆ alkenyl group , optionally substituted C ₂ even though -C ₆ alkynyl group in R ^7, substituted ₃ may be _1-7 cycloalkyl group with R ^7, to which may be substituted with R ⁷ heterocyclyl group, with R ⁷ optionally substituted phenyl group, an aromatic substituted with R ⁷ heterocyclic group, optionally substituted with ^{R 7 (:?. ~,} 3 Ararukiru group, optionally substituted with R ⁷ substituted C also to be of a heterocyclyl group, an alkyl group of -C _3, or C substituted with optionally substituted aromatic heterocyclic group R ^7, represents a -C ₃ alkyl group; '

In each substituent in Substituent Group 1, R ^6a and R ^6b , R ^{6 a} and R ^6c , or R ^6b and R ^{6c, which} are present in one group, may be substituted with R ⁷ If it is ~ C ₆ alkyl group, a single ^{bond, -0 -, - NR 9 -} , or S (O) _q - ring structure membered 3-7 linked to one another via can be formed;

Q represents an integer from 0 to 2 R ⁷ represents a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group,; ~ Ji alkoxy group, C, -C ₄ alkoxycarbonyl group, C, -C ₄ alkylsulfonyl group, or Ci～C ₄ Arukirusu sulfinyl group Represent,

R ⁸ , and R ⁹ may be the same or different and may be substituted with R ⁷ (^ to (represents a ₆ alkyl group). Claim 3. R ³ is 1 to 6 fluorine atoms Optionally substituted {C! Ce alkyl group, C ₃

-C ₇ cycloalkyl group, a C ₄ -C ₉ (cycloalkyl) alkyl group};

The compound according to claim 1 or 2, or a medically acceptable salt thereof, wherein R ⁴ represents a hydrogen atom. Is claim 4. R ^3, it represents 1-6 substituents which may be an isobutyl group by fluorine atom; R ⁴ is a hydrogen atom, according to claim 1 or 2 A compound according, or a medically acceptable Salt. 5. The compound according to any one of claims 1 to 4, or a medically acceptable salt thereof, wherein Ar ¹ represents a C ₆ -C _{1 Q} aryl group. 6. The compound according to any one of claims 1 to 5, or a medically acceptable salt thereof, wherein m represents an integer of 1 to 3. Salts which represent the ^{N (R 6a) (R 6b} ), the compound of claim 6, or its medically acceptable - Claim 7. at least one R ^1, - OR ^{6 a,} or. Claim 8. -Ar ^1- (R ¹ ) _m force group represented by formula (2),

Formula (2)

In equation (2)

R ^la represents -OR ^6a or -N (R ^6a ) (R ^6b );

^Rlb represents a halogen atom, ^-R6a , ^-OR6a , or -N ( ^R6a ) ( ^R6b ), The compound or its medically acceptable salt as described in any one of Claims 1-4. Claim 9. -Ar ^1- (R ¹ ) _m is a group represented by the formula (3),

Formula (3)

In equation (3),

R ^lc represents -N (R ^{6 a} ) (R ^6b ),

R ^ld represents a group selected from Substituent Group 1 or a compound according to any one of claims 1 to 4, or a medically acceptable salt thereof. 10. At least one of the groups substituting R ¹ , R ¹ , R ⁵ , and R ⁵ represents —COOH. Compound or its medically acceptable

Claim 1 1. R ^1. Groups substituting the R ^1, R ^5, and at least one of the groups substituting the R ^5, represents a Shiano group, any of claims 1 or 3 to 9 Or a medically acceptable salt thereof. 12. The compound according to any one of claims 1 to 4, or a medically acceptable salt thereof, wherein A r ¹ represents an aromatic heterocyclic group. Claim 1 3. The compound according to any one of Claims 1 to 12, or a medically acceptable salt thereof, wherein Ar ² represents 0 _{6 to} 0 _{1 ()} aryl group. 14. A compound according to any one of claims 1 to 12, or a medically acceptable salt thereof, which represents an A r ² force aromatic heterocyclic group. Claim 1 5. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14, or a medically acceptable salt thereof, and a pharmaceutically acceptable carrier. 16. A cathebsin K inhibitor comprising the compound according to any one of claims 1 to 14 or a medically acceptable salt thereof as an active ingredient. [Claim 1] 7. The compound according to any one of claims 1 to 14 or a medically acceptable salt thereof as an active ingredient, osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, A medicament for treating or preventing a disease selected from the group consisting of hypercalcemia, bone metastasis of cancer, and bone pain.