JP2005272476A - Heteroaromatic pentacyclic compound and medicinal use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a protein tyrosine phosphatase 1B inhibitor or a curative medicine for diabetes mellitus, hyperlipemia, obesity or diabetes mellitus complications. <P>SOLUTION: The heteroaromatic pentacyclic compounds of general formula [I] [wherein, V is CH or N; W is S or O; R<SP>1</SP>and R<SP>2</SP>are H or the like; X is N(R<SP>4</SP>), O, S, SO<SB>2</SB>-N(R<SP>5</SP>), CO-N(R<SP>7</SP>) or the like; L is general formula [II] (wherein, R<SP>20</SP>, R<SP>21</SP>, R<SP>22</SP>and R<SP>25</SP>are H or the like; and E is an aryl or an aromatic heterocycle); R is COOH or the like; B is an aryl or the like; R<SP>3</SP>is H or the like; Y is C(R<SP>13</SP>)(R<SP>14</SP>)-N(R<SP>12</SP>), C(R<SP>13</SP>)(R<SP>14</SP>)-O, N(R<SP>11</SP>), O or the like; A is an alkylene; Z is an aryl and the like; and so on], its prodrugs or its pharmaceutically acceptable salts are provided. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a novel heteroaromatic 5-membered ring compound, and more specifically, a heteroaromatic 5-membered ring compound having protein tyrosine phosphatase 1B (PTP1B; Protein Tyrosine Phosphatase 1B) inhibitory activity or a pharmaceutically acceptable salt thereof. And a pharmaceutical composition containing the same.

Diabetes is a disease that causes various metabolic abnormalities, mainly chronic chronic hyperglycemia, and exhibits various symptoms based on hyperglycemia such as dry mouth, heavy drinking, polyuria, and weight loss. It is also known that when such a hyperglycemic state lasts for a long time, it causes various complications such as retinopathy, nephropathy, neuropathy, and myocardial infarction and cerebral infarction based on arteriosclerosis.
Diabetes is broadly classified as type I diabetes (IDDM; insulin-dependent diabetes mellitus), which causes absolute insulin deficiency due to pancreatic β-cell damage / destruction, and relative insulin deficiency, due to insulin resistance and decreased insulin secretion II Type diabetes mellitus (NIDDM; non-insulin dependent diabetes mellitus), special diabetes that develops secondarily due to genetic abnormalities and other diseases, and gestational diabetes are classified into four types. Among those diagnosed with type 2 diabetes, the ability to secrete insulin gradually declines over time, and eventually type 1 diabetes may occur.

  For diabetes, it is essential to improve the hyperglycemic state as described above, and to prevent the onset and progression of complications. Therefore, in addition to diet therapy and exercise therapy, various drugs are used. Therefore, a treatment for controlling the blood glucose level to be within a normal range has been attempted. Typical existing drugs include insulin preparations, insulin secretagogues that promote insulin secretion from pancreatic β cells (sulfonylureas, sulfonamides, phenylalanine derivatives, etc.), α-glucosidase inhibitors that delay sugar absorption, liver sugar Differentiation from fibroblasts to adipocytes via the action of a biguanide, a peroxisome proliferator-activated receptor (PPAR) agonist, which is believed to have angiogenesis inhibitory action but the detailed mechanism is unknown Insulin sensitivity enhancers (thiazolidinedione derivatives, etc.) that increase the number of cells that have insulin sensitivity and numerically increase the sensitivity. However, each of them has problems in terms of efficacy and safety (for example, secondary ineffectiveness due to pancreatic β-cell exhaustion in insulin secretagogues, hypoglycemia risk and obesity promotion, edema in insulin sensitivity enhancer and heart based on it) Adverse effects, anemia, overeating, obesity promotion and the presence of non-responders), and sufficient blood glucose control has not yet been achieved.

  By the way, when looking at the sugar metabolism of the living body, the energy source and constituent materials of the living body are intermittently taken into the body, while the brain, for example, consumes glucose without interruption. Under such circumstances, blood sugar levels are kept almost constant, and such blood sugar control is possible because of hormones involved in blood sugar control, metabolism in organs, carbohydrates between organs, etc. Interaction. Among them, the action of insulin, which is a hormone particularly related to blood glucose regulation, is important, and it is considered that the disorder, that is, insulin resistance and insulin secretion decrease are deeply involved in diabetes.

Insulin is secreted from pancreatic β-cells and binds to insulin receptors, which are receptor tyrosine kinases on the membrane surface of skeletal muscle cells and adipocytes, which are target cells, and then tyrosine residues in the intracellular domain are autophosphorylated. Oxidized. Thereafter, IRS (insulin receptor substrate), which is a substrate of insulin receptor, APS (adapte)
t protein residues (such as protein protein PH and SH2 domain) are phosphorylated, and the PI ₃ kinase-Akt pathway is activated to transfer the glucose transporter onto the cell membrane, causing glucose uptake and the sugars in the blood. The concentration decreases. On the other hand, there is a tyrosine phosphatase that performs tyrosine dephosphorylation that negatively regulates intracellular signal transduction by insulin, and suppresses its activation. Thus, tyrosine phosphorylation plays a central role in insulin action, but considering that tyrosine phosphorylation is determined by the balance of the activity of tyrosine kinase, a phosphorylating enzyme, and tyrosine phosphatase, a dephosphorylating enzyme. Tyrosine phosphatases, together with tyrosine kinases, are thought to play an important regulatory role directly involved in insulin signaling.

  At present, tyrosine phosphatase forms a large gene family, and more than 70 kinds of isozymes have been reported. Among them, protein tyrosine phosphatase 1B (PTP1B; Protein Tyrosine Phosphatase 1B) is a major phosphatase involved in insulin signal transduction. It is believed that. In particular, it is observed that the gene expression of PTP1B is increased in high glucose culture, its intracellular localization is changed, tyrosine phosphorylation of insulin receptor and IRS-1 is decreased, and insulin resistance is induced (non-patented) References 1 and 2), the introduction of PTP1B wild type disrupted the translocation of the sugar transporter GLUT4, but the effect was not observed in phosphatase activity-deficient mutants. Further, insulin sensitivity was enhanced in PTP1B knockout mice. Moreover, since it becomes obesity resistant to a high-fat diet (Non-patent Document 3), this enzyme may be a target for enhancing the action from insulin activation to glucose uptake caused by insulin. There is sex. In fact, it has been recognized that vanadic acid, which has been known as a tyrosine phosphatase inhibitor, exhibits an insulin-like action in animal experiments and the like.

  Thus, drugs that suppress and / or inhibit the activation of such tyrosine phosphatases, particularly PTP1B, may inhibit glucose uptake by inhibiting the negative regulation of the insulin receptor activation signal via dephosphorylation. Can be a new type of anti-diabetic agent that lowers blood glucose based on direct enhancement of insulin action. Moreover, application to various disease therapeutic agents such as obesity and neurodegenerative diseases can also be expected.

In recent years, various reports have been made on compounds aimed at treating diseases such as diabetes by inhibiting protein tyrosine phosphatase.
For example, Patent Document 1 discloses a phosphonic acid derivative having a PTP1B inhibitory action. However, this publication does not disclose a compound having a structure such as the compound of the present invention, nor does it contain a statement to suggest it.

  Patent Document 2 (Patent Document 3) discloses arylacrylic acid derivatives useful as protein tyrosine phosphatase inhibitors. However, this publication does not disclose a compound having a structure such as the compound of the present invention, nor does it contain a statement to suggest it.

  Patent Document 4 (Patent Document 5) discloses a thiazole compound having a protein tyrosine phosphatase inhibitory action. However, this publication does not disclose a compound having a structure such as the compound of the present invention, nor does it contain a statement to suggest it.

Patent Document 6 discloses a naphtho [2,3-B] heteroal-4-yl derivative, Patent Document 7 discloses an oxa / thiazole-aryl-carboxylic acid derivative, Patent Document 8 and Patent Document 9 describe 11-aryl- Benzo [B] naphtho [2,3-D] furan and 11-aryl-benzo [B] naphtho [2,3-D] thiophene derivatives include biphenyl-oxo-
Acetic acid derivatives, 2,3,5-substituted biphenyl derivatives in Patent Document 11, biphenyl-sulfonyl-aryl-carboxylic acid derivatives in Patent Document 12, benzothiophene, benzofuran and indole derivatives in Patent Document 13, Patent Document 14 discloses furan, benzofuran and thiophene derivatives, Patent Document 15 discloses aryl-oxo-acetic acid derivatives, Patent Document 16 discloses 1-aryl-dibenzothiophene derivatives, and Patent Document 17 discloses 4-aryl-1 -Oxa-9-thia-cyclopenta [B] fluorene derivatives and Patent Document 18 disclose that benzophenone derivatives each have a protein tyrosine phosphatase inhibitory action. However, these gazettes do not disclose a compound having a structure such as the compound of the present invention, nor a statement that suggests it.

The following compounds have been reported as compounds having a thiazole, thiophene or oxazole structure.
Patent Document 19 describes 2-substituted thiazole derivatives. However, the compound of the same publication has a carbamoyl group at the terminal of the substituent at the 2-position of the thiazole ring, and there is no disclosure of a compound having a structure such as the compound of the present invention or a statement to suggest it. Moreover, the compound of the publication is useful as an antibacterial agent and an analgesic, and there is no disclosure about its usefulness as a PTP1B inhibitor, and there is no description suggesting it.

  Patent Document 20 describes 2-anilino-4-phenylthiazole derivatives. However, the compound of the publication has an anilino group substituted with a hydroxyl group or a carboxyl group at the 2-position of the thiazole ring, a phenyl group at the 4-position, and a substituent at the 2-position of the 4-position phenyl group. Therefore, there is no disclosure of a compound having a structure such as the compound of the present invention nor a statement to suggest it. Moreover, the compound of the publication is useful as a CRF (corticotropin releasing factor) antagonist, and there is no disclosure about its usefulness as a PTP1B inhibitor, and there is no description suggesting it.

  Patent Document 21 includes a general formula.

[Wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a substituted phenyl group, a pyridyl group or a substituted pyridyl group, and R ³ represents a hydroxyl group, a lower alkoxy group or —N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom or a lower alkyl group), R ⁴ is a hydrogen atom or a lower alkyl group, and X is An amino group, an amide group, a carbonyl group, an alkylene group, an oxygen atom or a sulfur atom]. However, the publication does not disclose a compound having a structure such as the compound of the present invention, and there is no description suggesting it. Moreover, the compound of the publication is useful as an anti-inflammatory agent, and the disclosure as to the usefulness as a PTP1B inhibitor is not found, and there is no description suggesting it.

Patent Document 22 describes 4-phenylthiazole derivatives. However,
The compound of the publication has a phenyl group at the 4-position of the thiazole ring and a substituent such as halogen at the 2-position of the 4-position phenyl group, and discloses a compound having a structure such as the compound of the present invention. There is no statement to suggest this. Moreover, the compound of the publication is useful as a pesticidal agent, and there is no disclosure about its usefulness as a PTP1B inhibitor, and there is no description suggesting it.

  Patent Document 23 includes a general formula.

[Wherein R ⁶ represents a hydroxyl group or a protective prodrug site, R ⁷ represents a hydrogen atom, a carboxy group, an arylaminocarbonyl group, an aroyl group, an aryl group, an alkylaminocarbonyl group, an aminocarbonyl group, an alkenylaminocarboxy group, Hydroxyl group, alkoxy group, ether, thiol, amino group-containing heterocyclic group or protective prodrug moiety, R ⁸ is a hydrogen atom or alkyl group that may be bonded to D to form a ring, R ⁹ is lower alkyl Group or hydrogen atom, Q is a bond, oxygen atom, sulfur atom, CR ³ OH, CR ³ SH, CR ³ NR ^3a R ^3b , NR ³ , (CR ³ R ^3a ) _n , O (CR ³ R ^3b ) _n Or (CR ³ R ^3a ) _n O (CR ^3b R ^3c ) _n (wherein n represents 0 or an integer of 1 to ³ , and R ³ , R ^3a , R ^3b and R ^3c are each independently a hydrogen atom) , May be substituted Chain, C _1-6 cyclic alkyl group or branched, C _2-6 alkenyl group, an acyl group, an arylalkyl group, an aryloxycarbonyl group, an arylaminocarbonyl group, an arylalkylsulfonyl group or an aryl group) , G represents a linking site, M represents an anchor site, J represents a bond, an alkylene group, an alkenylene group or an alkynylene group, D represents a hydrogen atom or an alkoxy group which may combine with G, M or Q to form a ring. An amine, an alkyl group, an alkenyl group, an alkynyl group, an aryl group or a heteroaryl group, t is 0 or 1, p is 0 or an integer of 1 to 5, and q is an integer of 0 or 1 to 3. ,
And
General formula

[Wherein P ⁴ is a carboxy group, a cleavable prodrug moiety, COOP ^{4 ′} , (CH ₂ ) _1-4 SP ^{4 ′} or C (O) NP ^{4 ′} P ^{4 ″} , R ⁷ is a hydrogen atom Carboxy group, optionally substituted lower alkyl ester, lower alkenyl ester, ester added with secondary amine substituted with lower alkyl, arylaminocarbonyl group, aroyl group, aryl group, alkylaminocarbonyl group, aminocarbonyl group , COOR ^{7 ′} , CONR ^{7 ′} R ^{7 ″} , hydroxyl group, ether, thiol, amino group, (CH ₂ ) _1-4 SR ^{7 ′} , heterocyclic group or cleavable prodrug moiety, P ^{4 ′} , P ^{4 ″} , R ^{7 ′} and R ^{7 ″} each independently represents a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or an optionally substituted aryl group, R ⁸ is a hydrogen atom, an alkyl group or D R ⁹ is a lower alkyl group or a hydrogen atom, Q is a bond, oxygen atom, sulfur atom, CR ³ OH, CR ³ SH, CR ³ NR ^3a R ^3b , NR ³ , (CR ³ R ^3a ) _N , O (CR ³ R ^3b ) _n or (CR ³ R ^3a ) _n O (CR ^3b R ^3c ) _n (wherein n represents 0 or an integer of 1 to 3, R ³ , R ^3a , R ^3b and R ^3c are each independently a hydrogen atom, an optionally substituted C _1-6 linear or branched alkyl group, a C _2-6 linear or branched alkenyl group, an aryloxycarbonyl group, An arylaminocarbonyl group, an arylalkylsulfonyl group, an arylalkyl group, an optionally substituted acyl group, an aryl group or a C _3-8 ring _optionally substituted with up to 4 heteroatoms), P ^2a , P ^2b, P ^3a and P ^3b are each independently hydrogen or substituted by Good linear, branched or cyclic C _1-5 alkyl group, G is a linking moiety, M is an anchor site, J is a bond, an alkylene group, an alkenylene group or an alkynylene group, D is a hydrogen atom, An alkyl group, an alkenyl group, an alkynyl group or an aryl group, or may combine with G, M or Q to form a ring, t is 0 or 1, p is 0 or an integer of 1 to 5, q represents 0 or an integer of 1 to 3]
A compound represented by
-NR ^'R' 'as examples of the anchor site in the general ^{formula, -CONR' R '', -S} (O) 2 NR 'R'', -S (O) 0-2 R', -NR ' ^{R '', -O (CR '} R'') 0-2 CF 3, -COR', -CO 2 R ' or ^-OR' (wherein, R ^{', R''are} each independently hydrogen atom, A thiazole group and an oxazole having an aryl group or a heteroaryl group substituted with a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or an aryl group which may be substituted) The groups are described as covalent linkages and C _1-6 alkyl groups as examples of linking sites, respectively.
Furthermore, the general formula

Wherein, M is carbocyclic group, a heterocyclic group, or CONR ^{'R' '(wherein, R',} R ^'' are each independently hydrogen atom, C _1-6 alkyl groups, C _2-6 alkenyl groups the C _2-6 show an alkynyl group, or an optionally substituted aryl group), Q is a bond, an oxygen atom, a sulfur ^{atom, CR 3 OH, CR 3 SH} , CR 3 NR 3a R 3b, NR 3, (CR ³ R ^3a ) _n , O (CR ³ R ^3b ) _n or (CR ³ R ^3a ) _n O (CR ^3b R ^3c ) _n (wherein n represents 0 or an integer of 1 to 3, R ³ , R ^3a , R ^3b and R ^3c are each independently a hydrogen atom, an optionally substituted branched, cyclic or linear C _1-6 alkyl group, a C _2-6 alkenyl group, an acyl group, an arylalkyl group, An aryloxycarbonyl group, an arylaminocarbonyl group, an arylalkylsulfonyl group or an aryl group)
, K is an independently selected secondary linking site, L is an independently selected secondary anchor site, P ⁴ is a hydrogen atom, a carboxy group, (CH ₂ ) _1-4 SP ^{4 ′} , A cleavable prodrug moiety, COOP ^{4 ′} or CONP ^{4 ′} P ^{4 ″} , where R ⁷ is a hydrogen atom, a carboxy group, an aroyl group, an aryl group, COOR ^{7 ′} , C (O) NR ^{7 ′} R ^{7 ″} , Hydroxyl group, ether, thiol, (CH ₂ ) _1-4 SR ^{7 ′} , heterocyclic group or cleavable prodrug moiety, P ^{4 ′} , P ^{4 ″} , R ^{7 ′} and R ^{7 ″} are independent of each other. A hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group or an aryl group which may be substituted, n is 0 or an integer of 1 to 4, and D is a hydrogen atom , Alkyl group, alkoxy group, alkenyl group, amine, hydroxyl group, alkynyl group, aryl group or heteroaryl group, Represents 0 or 1], and the secondary linking site contains a covalent bond, and the secondary anchor site contains an optionally substituted aryl group. .
However, the publication does not disclose a compound having a structure such as the compound of the present invention, and there is no description suggesting it. Moreover, the compound of the same publication is useful as an angiotensin converting enzyme (ACE) -2 regulator, and the disclosure as to its usefulness as a PTP1B inhibitor is not found.

Furthermore, there are the following reports of compounds having a thiazole or oxazole structure for the purpose of treating not only diabetes but also hyperlipidemia by inhibiting PTP1B.
Patent Document 24 includes a general formula.

An azole compound having a PTP1B inhibitory action represented by the formula, and that the compound is useful as a therapeutic drug for hyperlipidemia. However, in the compound of the publication, a nitrogen atom or a carbonyl group in the substituent A is adjacent to a carbon atom at the 2-position of thiazole or oxazole or is an alkylene; a bond between A and a benzene ring; and a substituent R ⁶ In which a nitrogen atom, an oxygen atom, a sulfur atom or a carbonyl group is adjacent to ring B, or through an alkylene or a single bond, reaches a ring structure. There is no disclosure of compounds having a structure such as Further, the publication does not indicate that the PTP1B inhibitory action of the compound is higher than the action on other protein tyrosine phosphatases.

In addition, the following is a report on a method of using a combination of multiple therapeutic agents for diabetes and other diseases.
Patent Document 25 discloses a combination of an insulin sensitivity enhancer and an insulin preparation, an insulin secretagogue, an α-glucosidase inhibitor, a biguanide, and the like. However, the publication does not disclose a PTP1B inhibitor or a receptor tyrosine kinase negative regulator inhibitor as in the present invention, and there is no description suggesting it.

  Patent Document 26 discloses a general formula.

Wherein M is selected from —SO ₂ —, —C═O, —C═S—, etc .; A ¹ is selected from a bond, C _1-6 alkyl, C _2-6 alkenyl, etc .; A Is selected from COOR ⁵ , CO-COOR ⁵ , PO ₃ R ⁵ R ^5, etc., wherein R ⁵ is each independently selected from a hydrogen atom and C _1-6 alkyl; R ¹ and R ² are independently represent hydrogen _{atom, C 1-6} alkyl _is selected from _{C 6-12} aryl and the like; ^{R 3} _is selected from _{C 6-12 aryl, C 3-10 heterocycle, C 6-12} aralkyl or the like;, Y is selected from a bond, —CH ₂ —, —CO—, etc .; Z is selected from C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, etc .; R ⁴ is a hydrogen atom, Selected from halogen, CN, NO _{2 and the} like. A thiophene derivative compound or a salt thereof is disclosed.
In Patent Document 27,

[Wherein, E ¹ and L are each independently a saturated or unsaturated 5- to 7-membered carbocyclic ring, a saturated or unsaturated 5- to 7-membered heterocyclic ring, a saturated or unsaturated bicyclic carbocyclic ring, etc. R is selected from —CH═C—R ² —, —C≡C—R ² , —C (R ² ) ═CH and the like; R ¹ is a hydrogen atom, —R, —NO ₂ etc. It is selected from; m is greater than 1, or 1; ^{R 2} is selected from hydrogen atom, halogen, alkyl or the like; W is a direct ^{bond, -CHR 2 -, - CH =} CR 2 - is selected from the like; E ² is selected from a saturated or unsaturated 5- to 7-membered carbocyclic ring, a saturated or unsaturated 5- to 7-membered heterocyclic ring, a bicyclic ring system, etc .; each X is independently a direct bond, substituted or unsubstituted Selected from C _1-4 methylene chain, O, etc., wherein the Xs at different positions may be the same or different; B is selected from a hydrogen atom, -halo, -CN, etc .; B ¹ is selected from B, B ¹ and B may be the same or different; p is 1 depending on the size of the ring Or more than 1; A is selected from R ¹ when o is 1, provided that when L is a ring having more than 5 atoms, o is 1 or 1 depending on the size of the ring More; V and V ¹ are each independently selected from R ¹ and N-alkyl substituted with carboxamidyl (CONHR), wherein the alkyl group is linear, branched, cyclic, or bicyclic And n is 0-4. A thiophene derivative compound is disclosed.

  Patent Document 28 includes the following formula:

Wherein B is N; A is selected from C _1-6 alkylsulfonyl, C _3-7 cycloalkylsulfonyl, C _3-7 cycloalkyl-C _1-6 alkylsulfonyl, each of which is a hydroxy group _{May be} mono-, _di- or trisubstituted with _C1-4 alkyl or halogen atoms;
Q is —C _2-8 alkylene-W—C _1-3 alkylene- or —C _3-8 alkylene-, where —C _3-8 alkylene- is a fluorine atom, C _1-4 alkyl, — X—C _1-5 may be substituted with up to 4 substituents independently selected from _1-5 alkylene-, etc., wherein X is independently selected from oxygen, nitrogen and sulfur atoms. Or a 5- or 6-membered aromatic ring optionally having 2 heteroatoms; Z is carboxyl, C _1-6 alkoxycarbonyl, tetrazolyl, etc .; K is a bond, C _1-8 alkylene, Thio (C _1-4 ) alkylene and the like, wherein the C _1-8 alkylene may be mono-substituted, and the K is mono-, di- or tri-substituted with a fluorine atom, methyl or chlorine atom. at best; and M, -Ar, -Ar ^-V-AP, a -Ar 1 -S-AP and the like, wherein Ar, Ar ¹ and AP are each independently an oxygen atom, 1 to 4 hetero atoms selected from sulfur atom and a nitrogen atom It is selected from partially saturated, fully saturated or fully unsaturated 5- to 8-membered rings which may have. Or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
Furthermore, Patent Document 29 (Patent Document 30) includes the following formula:

[In the formula, Ω is —NR ⁴⁶ R ⁴⁷ or —OR ⁴⁸ , wherein R ⁴⁶ and R ⁴⁷ are each independently selected from a hydrogen atom, alkyl, cycloalkyl, etc., and R ⁴⁸ is hydrogen. Selected from atoms, alkyl, alkynyl, etc .; B is a hydrogen atom or alkyl; Q is selected from a hydrogen atom, —OR ²² , —SR ^{22 and the} like, wherein R ²² is a hydrogen atom, alkyl, R ¹⁹ , R ²⁰ and R ²¹ are each independently selected from a hydrogen atom, a halogen atom, a hydroxy group, etc .; X is selected from alkyl, hydroxyl, aryl optionally substituted with a halogen atom, etc .; NH or S; N is 0 to 6; R ¹ and R ² are each selected from a hydrogen atom, alkyl and cycloalkyl. ] Are disclosed.

  Patent Document 31 includes the following formula:

[Wherein, R ¹ is a hydrogen atom, lower alkyl, cycloalkylthio or lower alkylthio, and R ² and R ³ are each independently a hydrogen atom or lower alkyl; or R ¹ and R ² are — CH ₂ —, —CO— or —C (CH ₃ ) ₂ — may be formed; R ⁴ is H 2 or O; R ⁵ is a hydrogen atom, substituted or unsubstituted lower alkyl, lower alkenyl. R ⁶ and R ⁷ are each independently selected from a hydrogen atom, —C (O) NHCHR ¹³ CO ₂ R ¹⁴ , substituted or unsubstituted lower alkyl, etc., wherein R ¹³ is is selected from lower alkyl and substituted or unsubstituted, R ¹⁴ is a hydrogen atom or a lower alkyl, or R ⁶ and R ⁷ may form an aryl or heterocyclyl; R ⁸ and R ⁹ Germany respectively And a hydrogen atom, a substituted or unsubstituted lower alkyl, selected from cycloalkyl, etc., ^{and, R 12} is ^NR 9, S or O. Or a pharmaceutically acceptable salt thereof.

  Patent Literature 32 and Patent Literature 33 include the following formula:

[Wherein, R ¹ is selected from a hydrogen atom, an optionally substituted hydrocarbon group, and an optionally substituted heterocyclic group; at least one of R ² and R ³ is a hydrogen atom, Is an optionally substituted pyridyl or an optionally substituted aromatic hydrocarbon group, the other is an optionally substituted pyridyl; and X is an optionally oxidized sulfur atom, oxygen atom or formula A group represented by NR ⁴ , wherein R ⁴ is a hydrogen atom, an optionally substituted hydrocarbon group, or acyl; Or a salt thereof (these may be N-oxidized).

  Patent Document 34 includes the following formula:

Wherein R ¹ is an optionally substituted alkyl, cycloalkyl, tricycloalkyl or an optionally substituted arylheterocyclic group; and R ² is a hydrogen atom or a halogen atom; Or R ¹ and R ² may be taken together with adjacent atoms to form a cycloalkene ring or an N-containing heterocycle; R ³ is selected from a hydrogen atom, a halogen atom, OH, etc .; R ⁴ Is selected from a hydrogen atom, an acyl group, CN, etc .; A is an alkylene, alkenylene or single bond; X is a single bond, O or S; and Y is O or S. Or a salt thereof.
However, none of these publications disclose a compound having a structure as in the present invention, nor a statement that suggests it.
International Publication No. 00/17211 Pamphlet Japanese National Patent Publication No. 11-508919 US Pat. No. 5,770,620 International Publication No. 98/27092 Pamphlet US Pat. No. 6,080,772 WO99 / 58522 pamphlet WO99 / 58511 pamphlet International Publication No. 99/58521 Pamphlet US Pat. No. 6,110,962 International Publication No. 99/58518 Pamphlet International Publication No. 99/61419 Pamphlet International Publication No. 99/58520 pamphlet International Publication No. 99/61435 Pamphlet US Pat. No. 6,103,708 US Pat. No. 6,110,963 US Pat. No. 6,001,867 US Pat. No. 6,057,316 US Pat. No. 6,063,815 International Publication No. 00/45635 Pamphlet Special Table 2000-504039 JP-A-4-154773 International Publication No. 94/08882 International Publication No. 02/39997 Pamphlet JP 2003-231679 A Japanese Patent Laid-Open No. 9-67271 International Publication No. WO02 / 100846 Pamphlet International Publication No. WO02 / 34711 Pamphlet International Publication No. WO 98/28264 Pamphlet International Publication No. WO01 / 26656 Pamphlet JP 2003-511416 A International Publication No. WO97 / 30053 Pamphlet International Publication No. WO99 / 21555 Pamphlet JP 2000-302680 A JP-A-5-202040 J. et al. Biol. Chem. 1995, Vol. 270, p. 7724-7730. J. et al. Biochem. (Tokyo), 1998, Vol. 123, p. 813-820. Science, 1999, 283, p. 1544-1548.

It is an object of the present invention to have an excellent selective PTP1B inhibitory action and a receptor tyrosine kinase negative regulator inhibitory action based thereon, a therapeutic drug for diabetes, a therapeutic drug for hyperlipidemia, obesity or diabetic complications, neurodegenerative disease It is to provide a compound useful as a therapeutic agent for such diseases.
Another object of the present invention is to provide a PTP1B inhibitor, a therapeutic drug for diabetes, a therapeutic drug for hyperlipidemia, a therapeutic drug for obesity, or a therapeutic drug for diabetic complications.

As a result of intensive studies to achieve the above-mentioned object, the present inventors have found that the heteroaromatic 5-membered ring compound represented by the following general formula [I] exhibits a high PTP1B inhibitory activity, and other than that, It has low inhibitory activity against protein tyrosine phosphatase, that is, it has an excellent selective PTP1B inhibitory action not found in conventional compounds, and is a PTP1B inhibitor, antidiabetic agent, antihyperlipidemic agent, antiobesity agent or diabetic complication It was found useful as a therapeutic agent, and the present invention was completed.
The present invention relates to compounds shown in the following [1] to [113] and pharmaceutical uses thereof.
[1] General formula [I]

[Where,
V represents = N- or = CH-;
W represents -S- or -O-;
m represents 0, 1 or 2;
R ¹ and R ² each independently represents a hydrogen atom or a C _1-4 alkyl group;
X represents —N (R ⁴ ) —, —N (R ⁵ ) —CO—O—, —SO ₂ —N (R ⁵ ) —, —N (R ⁵ ) —SO ₂ —, —N (R ⁶ ). ^{_{-SO 2 -N (R 5) -}} , - CO-N (R 7) -, - N (R 8) -CO -, - N (R 9) -CO-N (R 5) -, - N ( _{^{R 10) - (CH 2)}} k -N (R 5) -, - N (R 10) - (CH 2) k -N (R 5) -CO -, - C (R 10) = N-N ( ^{R 7) -, - N (} R 10) - (CH 2) k -CH (R 6) -, - O -, - S- or -SO ₂ -

(Where
k represents 0 or an integer of 1 to 4,
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently
(1) hydrogen atom,
(2) C _1-6 alkyl group (the C _1-6 alkyl group is
(a) an optionally substituted aryl group,
(b) an optionally substituted aromatic heterocyclic group,
(c) a carboxy group,
(d) a C _1-4 alkoxycarbonyl group,
(e) -CO-N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, a C _1-6 alkyl group (the C _1-6 The alkyl group is selected from the group consisting of an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C _1-4 alkoxy group and an optionally substituted aryloxy group. Or may be combined with the nitrogen atom to which they are attached to form an indoline ring, or may further comprise a nitrogen atom, an oxygen atom and a sulfur atom A 5- to 7-membered heterocycle which may contain at least one heteroatom selected from the group),
(f) -N (R ¹⁵ ) (R ¹⁶ )
Wherein R ¹⁵ and R ¹⁶ are as described above,
(g) -O-R ¹⁷
(Wherein R ¹⁷ is a hydrogen atom, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group or a C _1-6 alkyl group (the C _1-6 alkyl group is an optionally substituted aryl) Substituted with a substituent selected from the group consisting of a group, an optionally substituted aromatic heterocyclic group, an optionally substituted C _1-4 alkoxy group and an optionally substituted aryloxy group. Show)),
(h) -CO-R ¹⁷
(Wherein R ¹⁷ is as described above),
(i) -SO ₂ -R ¹⁷
(Wherein R ¹⁷ is as described above) or
(j) _optionally substituted with a C _3-7 cycloalkyl group),
(3) -CO-N (R ¹⁵ ) (R ¹⁶ )
Wherein R ¹⁵ and R ¹⁶ are as described above,
_{(4) -SO 2 -N (R} 15) (R 16)
Wherein R ¹⁵ and R ¹⁶ are as described above,
(5) -CO-R ¹⁷
(Wherein R ¹⁷ is as described above),
(6) -SO ₂ -R ¹⁷
(Wherein R ¹⁷ is as described above),
(7) an optionally substituted aryl group,
(8) represents an optionally substituted aromatic heterocyclic group, or
(9) R ⁴ and R ¹ together

Wherein i and j each independently represents 0, 1 or 2, and R ² is as described above,
(10) R ⁵ and R ⁹ together

(Wherein a and b each independently represent 0, 1 or 2),
(11) R ⁵ and R ¹⁰ together

(Wherein k1 and c each independently represents 0 or an integer of 1 to 4),
(12) R ⁵ and R ¹⁰ together

(Wherein d and e each independently represent 0, 1 or 2),
(13) R ⁶ and R ¹⁰ together

Wherein k1 and c are as described above, or
(14) R ⁷ and R ¹⁰ together

Wherein R ^{10 ′} represents a hydrogen atom or a C _1-6 alkyl group);
n represents 0 or an integer of 1 to 4;
p represents 0 or 1;
L is
(1)

(Where
R ²⁰ is
(a) a hydrogen atom,
(b) represents a C _1-6 alkyl group, or
(c) Together with R ⁴ or R ⁸

(In the formula, n1 and q each independently represent 0 or an integer of 1 to 4, and R ^{9 ′} represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a carboxy group or a C _1-6 alkoxy group. May be formed), or
(d) Together with R ⁴

(Wherein u and v each independently represent 0, 1 or 2),
R ²¹ is a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group), substituted An optionally substituted aryl group or an optionally substituted aromatic heterocyclic group),
(2)

(Where
E represents an aryl group or an aromatic heterocyclic group,
R ²² is
(a) a hydrogen atom,
(b) a halogen atom,
(c) a C _1-4 alkyl group,
(d) a C _1-4 alkoxy group that may be substituted with a carboxy group,
(e) a C _1-6 alkylthio group,
(f) a nitro group,
(g) -N (R ²³ ) (R ²⁴ )
(Wherein R ²³ and R ²⁴ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _1-4 alkylcarbonyl group (the C _1-4 alkylcarbonyl group is an amino group, C _1-4 An alkylamino group or a di (C _1-4 alkyl) amino group) or a C _1-4 alkylsulfonyl group), or
(h) Together with R ⁴

(Wherein n2 and w each independently represent 0 or an integer of 1 to 3, and E is as described above),
(i) Together with R ⁴

(Wherein n3 and x each independently represents 0 or 1, E is as described above),
(j) Together with R ⁷

(Wherein n4 and y each independently represent 0, 1 or 2, and E is as described above),
(k) Together with R ⁷

(Wherein n5 and z each independently represent 0 or 1, and E is as described above),
(l) Together with R ⁸

In which n2 and w each independently represent 0 or an integer from 1 to 3 and E is as described above, or (m) together with R ⁴ The

Where E is as described above, or
(3)

(Where
R ²⁰ , R ²¹ and E are as described above;
R ²⁵ is
(a) a hydrogen atom,
(b) a halogen atom,
(c) a C _1-4 alkyl group,
(d) a C _1-4 alkoxy group that may be substituted with a carboxy group,
(e) a C _1-6 alkylthio group,
(f) a nitro group or
(g) -N (R ²³ ) (R ²⁴ )
Wherein R ²³ and R ²⁴ are as described above;
R represents —COO (R ¹⁹ ), —A ¹ —COO (R ¹⁹ ) or —O—A ¹ —COO (R ¹⁹ ).
(Wherein A ¹ represents a C _1-4 alkylene group and R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group);
B represents an aryl group or an aromatic heterocyclic group;

R ³ is
(1) hydrogen atom,
(2) a halogen atom,
(3) C _1-8 alkyl group,
(4) C _1-6 alkoxy group,
(5) C _1-6 alkylamino group,
(6) a di (C _1-6 alkyl) amino group,
(7) cyano group,
(8) Nitro group,
(9) C _1-4 haloalkyl group,
(10) -S-R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group),
(11) -SO-R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group),
(12) —SO ₂ —R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group),
(13) an aryl group or
(14) represents a heterocyclic group;

Y represents —O—, —S—, —SO—, —SO ₂ —, —N (R ¹¹ ) —, —N (R ¹² ) —CO—, —N (R ¹² ) —SO ₂ —, —SO. ₂ -N (R ¹² )-, -C (R ¹³ ) (R ¹⁴ )-, -CO-, -C (R ¹³ ) (R ¹⁴ ) -N (R ¹² )-, -CO-N (R ¹² ) - or ^{-C (R 13) (R 14} ) -O-
(Where
R ¹¹ is
(1) hydrogen atom,
(2) C _1-8 alkyl group (the C _1-8 alkyl group is
(a) a C _3-7 cycloalkyl group,
(b) an optionally substituted aryl group,
(c) an optionally substituted heterocyclic group,
(d) a hydroxyl group,
(e) a C _1-4 alkylamino group and
(f) optionally substituted with a substituent selected from the group consisting of di (C _1-4 alkyl) amino groups),
(3) C _2-4 alkenyl group,
(4) C _1-4 alkylsulfonyl group,
(5) represents a C _1-4 alkylcarbonyl group (the C _1-4 alkylcarbonyl group may be substituted with a hydroxyl group or a C _1-4 alkoxy group), or
(6) Together with R ³

Wherein t is an integer from 1 to 4 and B is as described above,
R ¹² is
(1) hydrogen atom,
(2) C _1-8 alkyl group (the C _1-8 alkyl group is
(a) a C _3-7 cycloalkyl group,
(b) an optionally substituted aryl group,
(c) an optionally substituted heterocyclic group,
(d) a hydroxyl group,
(e) a C _1-4 alkylamino group and
(f) optionally substituted with a substituent selected from the group consisting of di (C _1-4 alkyl) amino groups),
(3) C _2-4 alkenyl group,
(4) C _1-4 alkylsulfonyl group or
(5) a C _1-4 alkylcarbonyl group (the C _1-4 alkylcarbonyl group may be substituted with a hydroxyl group or a C _1-4 alkoxy group);
R ¹³ and R ¹⁴ each independently represent a hydrogen atom, a C _1-4 alkyl group, or together with the carbon atom to which they are bonded, may form a C _3-7 cycloalkane; Or a 5- to 7-membered heterocycle which may contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, together with the carbon atom to which they are bonded. (But may be)
m is 0, p is 1, and L is

(Wherein R ²⁰ and R ²¹ each represent a hydrogen atom, E represents a phenyl group, R ²² represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group or a nitro group. And R ²⁵ represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group or a nitro group),
Y is
^{-C (R 13) (R 14} ) -N (R 12) -, - CO-N (R 12) - or ^{-C (R 13) (R 14} ) -O- ( wherein, R ^12, R ¹³ And R ¹⁴ is as described above));
s represents 0 or 1;
A represents a C _1-4 alkylene group which may be substituted with a C _3-7 cycloalkyl group;

Z is
(1) C _3-7 cycloalkyl group (the C _3-7 cycloalkyl group is an aryl group (the aryl group may be substituted with a halogen atom or a C _1-6 alkyl group) or an aromatic heterocyclic group ( The aromatic heterocyclic group may be substituted with a halogen atom or a C _1-6 alkyl group).
(2) Aryl group (the aryl group is
(a) a heterocyclic group which may be substituted with a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group,
(b) a C _3-7 cycloalkyl group _optionally substituted with a hydroxyl group, an oxo group, a halogen atom or a C _1-6 alkyl group,
(c) a carboxy group,
(d) a halogen atom,
(e) a C _1-8 alkyl group,
(f) a C _1-4 haloalkyl group,
(g) a C _1-4 alkylamino group,
(h) a di (C _1-4 alkyl) amino group,
(i) a C _1-6 alkylthio group,
(j) C _1-4 alkoxy group
(k) a C _1-4 alkylcarbonyl group and
(l) optionally substituted with a substituent selected from the group consisting of nitro groups),
(3) Aromatic heterocyclic group (the aromatic heterocyclic group is
(a) a heterocyclic group which may be substituted with a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group,
(b) a C _3-7 cycloalkyl group _optionally substituted with a hydroxyl group, an oxo group, a halogen atom or a C _1-6 alkyl group,
(c) a carboxy group,
(d) a halogen atom,
(e) a C _1-8 alkyl group,
(f) a C _1-4 haloalkyl group,
(g) a C _1-4 alkylamino group,
(h) a di (C _1-4 alkyl) amino group,
(i) a C _1-6 alkylthio group,
(j) a C _1-4 alkoxy group,
(k) a C _1-4 alkylcarbonyl group and
(l) optionally substituted with a substituent selected from the group consisting of a halogen atom or an aryl group optionally substituted with a C _1-4 haloalkyl group),
(4) Indanyl group or
(5) Piperazinyl group (the piperazinyl group is
(a) a phenyl group,
(b) a phenyl C _1-4 alkyl group,
(c) a benzoyl group optionally substituted with a halogen atom and
(d) optionally substituted with a substituent selected from the group consisting of phenyl C _1-4 alkoxycarbonyl groups)] or a prodrug thereof, or a pharmaceutically acceptable salt thereof Acceptable salt.

[2] General formula [I]

[Where,
V represents = N- or = CH-;
W represents -S- or -O-;
m represents 0, 1 or 2;
R ¹ and R ² each independently represents a hydrogen atom or a C _1-4 alkyl group;

X represents —N (R ⁴ ) —, —N (R ⁵ ) —CO—O—, —SO ₂ —N (R ⁵ ) —, —N (R ⁵ ) —SO ₂ —, —N (R ⁶ ). ^{_{-SO 2 -N (R 5) -}} , - CO-N (R 7) -, - N (R 8) -CO -, - N (R 9) -CO-N (R 5) -, - N ( _{^{R 10) - (CH 2)}} k -N (R 5) -, - O -, - S- or -SO ₂ -
(Where
k represents 0 or an integer of 1 to 4,
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are each independently
(1) hydrogen atom,
(2) C _1-6 alkyl group (the C _1-6 alkyl group is
(a) an optionally substituted aryl group,
(b) an optionally substituted aromatic heterocyclic group,
(c) a carboxy group,
(d) a C _1-4 alkoxycarbonyl group,
(e) -CO-N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, a C _1-6 alkyl group (the C _1-6 The alkyl group is selected from the group consisting of an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, an optionally substituted C _1-4 alkoxy group and an optionally substituted aryloxy group. Or may be combined with the nitrogen atom to which they are attached to form an indoline ring, or may further comprise a nitrogen atom, an oxygen atom and a sulfur atom A 5- to 7-membered heterocycle which may contain at least one heteroatom selected from the group),
(f) -N (R ¹⁵ ) (R ¹⁶ )
Wherein R ¹⁵ and R ¹⁶ are as described above,
(g) -O-R ¹⁷
(Wherein R ¹⁷ is a hydrogen atom, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group or a C _1-6 alkyl group (the C _1-6 alkyl group is an optionally substituted aryl) Substituted with a substituent selected from the group consisting of a group, an optionally substituted aromatic heterocyclic group, an optionally substituted C _1-4 alkoxy group and an optionally substituted aryloxy group. Show)),
(h) -CO-R ¹⁷
(Wherein R ¹⁷ is as described above),
(i) -SO ₂ -R ¹⁷
(Wherein R ¹⁷ is as described above) or
(j) _optionally substituted with a C _3-7 cycloalkyl group),
(3) -CO-N (R ¹⁵ ) (R ¹⁶ )
Wherein R ¹⁵ and R ¹⁶ are as described above,
_{(4) -SO 2 -N (R} 15) (R 16)
Wherein R ¹⁵ and R ¹⁶ are as described above,
(5) -CO-R ¹⁷
(Wherein R ¹⁷ is as described above),
(6) -SO ₂ -R ¹⁷
(Wherein R ¹⁷ is as described above),
(7) an optionally substituted aryl group,
(8) represents an optionally substituted aromatic heterocyclic group, or
(9) R ⁴ and R ¹ together

Wherein i and j each independently represents 0, 1 or 2, and R ² is as described above,
(10) R ⁵ and R ⁹ together

(Wherein a and b each independently represent 0, 1 or 2),
(11) R ⁵ and R ¹⁰ together

(Wherein k1 and c each independently represent 0 or an integer of 1 to 4), or
(12) R ⁵ and R ¹⁰ together

Wherein d and e each independently represents 0, 1 or 2);
n represents 0 or an integer of 1 to 4;
p represents 0 or 1;
L is
(1)

(Where
R ²⁰ is
(a) a hydrogen atom,
(b) represents a C _1-6 alkyl group, or
(c) Together with R ⁴

(Wherein n1 and q each independently represents 0 or an integer of 1 to 4), or
(d) Together with R ⁴

(Wherein u and v each independently represent 0, 1 or 2),
R ²¹ is a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group), substituted An optionally substituted aryl group or an optionally substituted aromatic heterocyclic group),
(2)

(Where
E represents an aryl group or an aromatic heterocyclic group,
R ²² is
(a) a hydrogen atom,
(b) a halogen atom,
(c) a C _1-4 alkyl group,
(d) a C _1-4 alkoxy group that may be substituted with a carboxy group,
(e) a C _1-6 alkylthio group,
(f) a nitro group,
(g) -N (R ²³ ) (R ²⁴ )
(Wherein R ²³ and R ²⁴ are each independently a hydrogen atom, a C _1-6 alkyl group, a C _1-4 alkylcarbonyl group (the C _1-4 alkylcarbonyl group is an amino group, C _1-4 An alkylamino group or a di (C _1-4 alkyl) amino group) or a C _1-4 alkylsulfonyl group), or
(h) Together with R ⁴

(Wherein n2 and w each independently represent 0 or an integer of 1 to 3, and E is as described above),
(i) Together with R ⁴

(Wherein n3 and x each independently represents 0 or 1, E is as described above),
(j) Together with R ⁷

(Wherein n4 and y each independently represent 0, 1 or 2, and E is as described above),
(k) Together with R ⁷

Wherein n5 and z each independently represent 0 or 1, and E is as described above, or
(l) Together with R ⁸

(Wherein n2 and w each independently represent 0 or an integer of 1 to 3, and E is as described above) or
(3)

(Where
R ²⁰ , R ²¹ and E are as described above;
R ²⁵ is
(a) a hydrogen atom,
(b) a halogen atom,
(c) a C _1-4 alkyl group,
(d) a C _1-4 alkoxy group that may be substituted with a carboxy group,
(e) a C _1-6 alkylthio group,
(f) a nitro group or
(g) -N (R ²³ ) (R ²⁴ )
Wherein R ²³ and R ²⁴ are as described above;
R represents —COO (R ¹⁹ ), —A ¹ —COO (R ¹⁹ ) or —O—A ¹ —COO (R ¹⁹ ).
(Wherein A ¹ represents a C _1-4 alkylene group and R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group);
B represents an aryl group or an aromatic heterocyclic group;

R ³ is
(1) hydrogen atom,
(2) a halogen atom,
(3) C _1-8 alkyl group,
(4) C _1-6 alkoxy group,
(5) C _1-6 alkylamino group,
(6) a di (C _1-6 alkyl) amino group,
(7) cyano group,
(8) Nitro group,
(9) C _1-4 haloalkyl group,
(10) -S-R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group),
(11) —SO—R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group) or
(12) —SO ₂ —R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group);
Y represents —O—, —S—, —SO—, —SO ₂ —, —N (R ¹¹ ) —, —N (R ¹² ) —CO—, —N (R ¹² ) —SO ₂ —, —SO. ₂ -N (R ¹² )-, -C (R ¹³ ) (R ¹⁴ )-, -CO-, -C (R ¹³ ) (R ¹⁴ ) -N (R ¹² )-, -CO-N (R ¹² ) - or ^{-C (R 13) (R 14} ) -O-
(Where
R ¹¹ is
(1) hydrogen atom,
(2) C _1-8 alkyl group (the C _1-8 alkyl group is
(a) a C _3-7 cycloalkyl group,
(b) an optionally substituted aryl group,
(c) an optionally substituted heterocyclic group,
(d) a hydroxyl group,
(e) a C _1-4 alkylamino group and
(f) optionally substituted with a substituent selected from the group consisting of di (C _1-4 alkyl) amino groups),
(3) C _2-4 alkenyl group,
(4) C _1-4 alkylsulfonyl group,
(5) represents a C _1-4 alkylcarbonyl group (the C _1-4 alkylcarbonyl group may be substituted with a hydroxyl group or a C _1-4 alkoxy group), or
(6) Together with R ³

Wherein t is an integer from 1 to 4 and B is as described above,
R ¹² is
(1) hydrogen atom,
(2) C _1-8 alkyl group (the C _1-8 alkyl group is
(a) a C _3-7 cycloalkyl group,
(b) an optionally substituted aryl group,
(c) an optionally substituted heterocyclic group,
(d) a hydroxyl group,
(e) a C _1-4 alkylamino group and
(f) optionally substituted with a substituent selected from the group consisting of di (C _1-4 alkyl) amino groups),
(3) C _2-4 alkenyl group,
(4) C _1-4 alkylsulfonyl group or
(5) a C _1-4 alkylcarbonyl group (the C _1-4 alkylcarbonyl group may be substituted with a hydroxyl group or a C _1-4 alkoxy group);
R ¹³ and R ¹⁴ each independently represent a hydrogen atom, a C _1-4 alkyl group, or together with the carbon atom to which they are bonded, may form a C _3-7 cycloalkane; Or a 5- to 7-membered heterocycle which may contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, together with the carbon atom to which they are bonded. (But may be)
m is 0, p is 1, and L is

(Wherein R ²⁰ and R ²¹ each represent a hydrogen atom, E represents a phenyl group, R ²² represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group or a nitro group. And R ²⁵ represents a hydrogen atom, a halogen atom, a C _1-4 alkyl group, a C _1-4 alkoxy group or a nitro group),
Y is
^{-C (R 13) (R 14} ) -N (R 12) -, - CO-N (R 12) - or ^{-C (R 13) (R 14} )
-O- (wherein R ¹² , R ¹³ and R ¹⁴ are as described above);
s represents 0 or 1;
A represents a C _1-4 alkylene group which may be substituted with a C _3-7 cycloalkyl group;

Z is
(1) C _3-7 cycloalkyl group (the C _3-7 cycloalkyl group is an aryl group (the aryl group may be substituted with a halogen atom or a C _1-6 alkyl group) or an aromatic heterocyclic group ( The aromatic heterocyclic group may be substituted with a halogen atom or a C _1-6 alkyl group).
(2) Aryl group (the aryl group is
(a) a heterocyclic group which may be substituted with a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group,
(b) a C _3-7 cycloalkyl group _optionally substituted with a hydroxyl group, an oxo group, a halogen atom or a C _1-6 alkyl group,
(c) a carboxy group,
(d) a halogen atom,
(e) a C _1-8 alkyl group,
(f) a C _1-4 haloalkyl group,
(g) a C _1-4 alkylamino group,
(h) a di (C _1-4 alkyl) amino group,
(i) a C _1-6 alkylthio group,
(j) a C _1-4 alkoxy group and
(k) optionally substituted with a substituent selected from the group consisting of C _1-4 alkylcarbonyl groups),
(3) Aromatic heterocyclic group (the aromatic heterocyclic group is
(a) a heterocyclic group which may be substituted with a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group,
(b) a C _3-7 cycloalkyl group _optionally substituted with a hydroxyl group, an oxo group, a halogen atom or a C _1-6 alkyl group,
(c) a carboxy group,
(d) a halogen atom,
(e) a C _1-8 alkyl group,
(f) a C _1-4 haloalkyl group,
(g) a C _1-4 alkylamino group,
(h) a di (C _1-4 alkyl) amino group,
(i) a C _1-6 alkylthio group,
(j) a C _1-4 alkoxy group,
(k) a C _1-4 alkylcarbonyl group and
(l) optionally substituted with a substituent selected from the group consisting of a halogen atom or an aryl group optionally substituted with a C _1-4 haloalkyl group),
(4) Indanyl group or
(5) Piperazinyl group (the piperazinyl group is
(a) a phenyl group,
(b) a phenyl C _1-4 alkyl group,
(c) a benzoyl group optionally substituted with a halogen atom and
(d) optionally substituted with a substituent selected from the group consisting of phenyl C _1-4 alkoxycarbonyl groups)] or a prodrug thereof according to [1] above Or a pharmaceutically acceptable salt thereof.

[3] In the general formula [I],
R ³ is
(1) hydrogen atom,
(2) a halogen atom,
(3) C _1-6 alkyl group or
(4) represents a C _1-4 alkoxy group;
Y represents —O—, —N (R ¹¹ ) —, —N (R ¹² ) —CO—, —C (R ¹³ ) (R ¹⁴ ) —, —C (R ¹³ ) (R ¹⁴ ) —N (R ^{12) -, - CO-N} (R 12) - or ^{-C (R 13) (R 14} ) -O- ( in the formula,
R ¹¹ is
(1) hydrogen atom,
(2) represents a C _1-8 alkyl group, or
(3) Together with R ³

(Wherein t represents 3 and B is as described in [2] above),
R ¹² represents a hydrogen atom or a C _1-8 alkyl group,
R ¹³ and R ¹⁴ each represent a hydrogen atom) (provided that
m is 0, p is 1, and L is

(Wherein R ²⁰ and R ²¹ each represent a hydrogen atom, E represents a phenyl group, R ²² represents a hydrogen atom, a C _1-4 alkoxy group or a nitro group, R ²⁵ represents a hydrogen atom, C _{1- 4 represents an} alkoxy group or a nitro group)
Y is
^{-C (R 13) (R 14} ) -N (R 12) -, - CO-N (R 12) - or ^{-C (R 13) (R 14} ) -O- ( wherein, R ^12, R ¹³ And R ¹⁴ is as described above));
s represents 0 or 1;
A represents a C _1-4 alkylene group;

Z is
(a) a C _3-7 cycloalkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group,
(b) a halogen atom,
(c) a C _1-8 alkyl group,
(d) a C _1-4 haloalkyl group,
(e) a di (C _1-4 alkyl) amino group,
(f) a C _1-6 alkylthio group and
(g) the heteroaromatic 5-membered ring compound or prodrug thereof according to the above [1], which represents an aryl group substituted with a substituent selected from the group consisting of C _1-4 alkylcarbonyl groups, or a pharmaceutically acceptable product thereof Possible salt.

[4] The 5-membered heteroaromatic member according to the above [3], wherein V is = N- and W is -S- or -O-, or V is = CH- and W is -S-. A ring compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[5] The heteroaromatic 5-membered ring compound according to the above [4], wherein Z is a phenyl group substituted with a C _1-8 alkyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[6] Y is —C (R ¹³ ) (R ¹⁴ ) —N (R ¹² ) — or —C (R ¹³ ) (R ¹⁴ ) —O— (wherein R ¹² , R ¹³ and R ¹⁴ are the same as above. [3] and s is 0, or Y is —O— or —N (R ¹¹ ) — (wherein R ¹¹ is as described in [3] above). A heteroaromatic 5-membered ring compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof according to [5] above, wherein s is 1 and A is a methylene group.

[7] The above [6], wherein V is = CH-, W is -S-, and the substitution position of B on the thiophene ring constituted by V and W is the 4-position or 5-position. Heteroaromatic 5-membered ring compounds or prodrugs thereof, or pharmaceutically acceptable salts thereof.

[8] The heteroaromatic 5-membered ring compound according to the above [7], wherein B is a phenyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[9] m is 1;
R ¹ and R ² are each a hydrogen atom;
X is —N (R ⁴ ) — or —O—.
(Where R ⁴ is
(a) an aryl group,
(b) an aromatic heterocyclic group which may be substituted with 1 to 3 C _1-8 alkyl groups, or
(c) -CO-N (R 15) (R 16)
(Wherein R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom or an aryl group (the aryl group may be substituted with 1 to 3 C _1-8 alkyl groups))
A C _1-6 alkyl group which may be substituted with
n is 0 or 1;
p is 0 or 1;
L is
(1)

(Wherein R ²⁰ together with R ⁴

In which u represents 1, v represents 1, and R ² is as described above,
R ²¹ represents a hydrogen atom) or
(2)

Wherein E represents an aromatic heterocyclic group and R ²² represents a hydrogen atom;
R is —COO (R ¹⁹ )
(Wherein R ¹⁹ represents a hydrogen atom), the heteroaromatic 5-membered ring compound of the above-mentioned [8] or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[10] The complex described in [9] above, wherein X is —N (R ⁴ ) (wherein R ⁴ is as described in [9] above), n is 1 and p is 0. An aromatic 5-membered ring compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[11] The heteroaromatic 5-membered ring compound or the prodrug thereof according to [10], wherein R ⁴ is a methyl group substituted with an aromatic heterocyclic group _optionally substituted with one C _1-8 alkyl group Or a pharmaceutically acceptable salt thereof.

[12] The heteroaromatic 5-membered ring compound or prodrug thereof according to [11] above, wherein the aromatic heterocycle according to [11] above is a thiazolyl group, oxazolyl group or benzimidazolyl group, or a pharmaceutically acceptable product thereof. salt.

[13] R ⁴ represents —CO—N (R ¹⁵ ) (R ¹⁶ ) (wherein R ¹⁵ represents a hydrogen atom, and R ¹⁶ represents an aryl group which may be substituted with one C _1-8 alkyl group) Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[14] The heteroaromatic 5 according to the above [6], wherein V is = N-, W is -S-, and the substitution position of B on the thiazole ring constituted by V and W is the 4-position. A membered ring compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[15] The heteroaromatic 5-membered ring compound according to the above [14], wherein B is a phenyl group, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[16] m is 0 or 1;
R ¹ and R ² are each independently a hydrogen atom or a C _1-4 alkyl group;
X is —N (R ⁴ ) —, —N (R ⁵ ) —CO—O—, —SO ₂ —N (R ⁵ ) —, —CO—N (R ⁷ ) —, —N (R ⁹ ) — ^{CO-N (R 5) -} , - N (R 10) - (CH 2) k -N (R 5) -, - O -, - S- or -SO ₂ -
(Where
R ⁴ is
(1) hydrogen atom,
(2) C _1-6 alkyl group (the C _1-6 alkyl group is
(a) an aryl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-8 alkyl group and a C _1-4 haloalkyl group;
(b) an aromatic heterocyclic group optionally substituted with 1 to 3 C _1-8 alkyl groups;
(c) a carboxy group,
(d) a C _1-4 alkoxycarbonyl group,
(e) -CO-N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an aryl group (the aryl group is a C _1-8 alkyl group, a C _1-4 alkoxy group, a carboxy group and a di (C _1-4 alkyl ) Which may be substituted with 1 to 3 substituents selected from the group consisting of amino groups), aromatic heterocyclic groups, C _1-6 alkyl groups (the C _1-6 alkyl groups are aryl groups) Which may be substituted), or together with the nitrogen atom to which they are attached, may further contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A good 5- to 7-membered heterocycle may be formed),
(f) -N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ each independently represents a hydrogen atom or an aryl group),
(g) -O-R ¹⁷
(Wherein R ¹⁷ represents an aryl group) or
(h) _optionally substituted with a C _3-7 cycloalkyl group),
(3) -CO-N (R ¹⁵ ) (R ¹⁶ )
Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an aryl group (the aryl group may be substituted with 1 to 3 C _1-8 alkyl groups), C _1-6 At least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may represent an alkyl group, or together with the nitrogen atom to which they are attached, form an indoline ring A 5- to 7-membered heterocyclic ring may be formed),
_{(4) -SO 2 -N (R} 15) (R 16)
(Wherein R ¹⁵ and R ¹⁶ each independently represents an aryl group or a C _1-6 alkyl group),
(5) -CO-R ¹⁷
Wherein R ¹⁷ is an aryl group (the aryl group may be substituted with 1 to 3 substituents selected from the group consisting of a C _1-8 alkyl group and a C _1-4 alkoxy group); An aromatic heterocyclic group or a C _1-6 alkyl group (the C _1-6 alkyl group is an aryl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C _1-8 alkyl group) , An aromatic heterocyclic group, a C _1-4 alkoxy group that may be substituted with an aryl group, or an aryloxy group that may be substituted with 1 to 3 C _1-8 alkyl groups) ),
(6) -SO ₂ -R ¹⁷
(Wherein R ¹⁷ represents an aryl group),
(7) represents an aryl group, or
(8) Together with R ¹

Wherein i and j each represent 1 and R ² is as described above,
R ⁵ represents a hydrogen atom or an aryl group or a C _1-6 alkyl group which may be substituted with a C _3-7 cycloalkyl group;
R ⁷ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁹ represents a hydrogen atom or a C _1-6 alkyl group,
k represents 2,
R ¹⁰ is
(1) hydrogen atom,
(2) represents a C _1-6 alkyl group, or
(3) Together with R ⁵

(Wherein k1 and c each represents 2));
n is 0 or an integer of 1 to 3;
p is 0 or 1;
L is
(1)

(Where
R ²⁰ is
(a) a hydrogen atom,
(b) represents a C _1-6 alkyl group, or
(c) Together with R ⁴

(Wherein n1 and q each independently represents an integer of 1 to 3), or
(d) Together with R ⁴

(Wherein u represents 1 and v represents 1),
R ²¹ represents a hydrogen atom, a C _1-6 alkyl group (the C _1-6 alkyl group may be substituted with an aryl group which may be substituted with 1 to 3 halogen atoms) or an aryl group) Or
(2)

(Where
E represents an aryl group or an aromatic heterocyclic group,
R ²² is
(a) a hydrogen atom,
(b) a C _1-4 alkoxy group which may be substituted with a carboxy group,
(c) a nitro group,
(d) -N (R ²³ ) (R ²⁴ )
(Wherein R ²³ and R ²⁴ are each independently a hydrogen atom, a C _1-4 alkylcarbonyl group (the C _1-4 alkylcarbonyl group is a C _1-4 alkylamino group or di (C _1-4 Alkyl) optionally substituted with an amino group) or C _1-4 alkylsulfonyl group), or
(e) Together with R ⁴

(Wherein n3 represents 0, x represents 1 and E is as described above));
R is —COO (R ¹⁹ )
(Wherein R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group), the heteroaromatic 5-membered ring compound or a prodrug thereof according to the above [15], or a pharmaceutically acceptable salt thereof.

[17] The heteroaromatic 5-membered ring compound according to the above [16], wherein m is 1, and R ¹ and R ² are each a hydrogen atom, or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[18] The complex according to [17], wherein X is —N (R ⁴ ) (wherein R ⁴ is as described in [16] above), n is 1 and p is 0. An aromatic 5-membered ring compound or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[19] R ⁴ is
(a) an aryl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-8 alkyl group and a C _1-4 haloalkyl group;
(b) an aromatic heterocyclic group optionally substituted with 1 to 3 C _1-8 alkyl groups;
(c) a carboxy group,
(d) a C _1-4 alkoxycarbonyl group,
(e) -CO-N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an aryl group (the aryl group is a C _1-8 alkyl group, a C _1-4 alkoxy group, a carboxy group and a di (C _1-4 alkyl ) Which may be substituted with 1 to 3 substituents selected from the group consisting of amino groups), aromatic heterocyclic groups, C _1-6 alkyl groups (the C _1-6 alkyl groups are aryl groups) Which may be substituted), or together with the nitrogen atom to which they are attached, may further contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A good 5- to 7-membered heterocycle may be formed),
(f) -N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ each independently represents a hydrogen atom or an aryl group),
(g) -O-R ¹⁷
(Wherein R ¹⁷ represents an aryl group) or
(h) the heteroaromatic 5-membered ring compound or prodrug thereof according to [18] above, which is a C _1-6 alkyl group _optionally substituted with a C _3-7 cycloalkyl group, or a pharmaceutically acceptable salt thereof; salt.

[20] The heteroaromatic 5-membered ring compound or the prodrug thereof according to [19], wherein R ⁴ is a methyl group substituted with an aromatic heterocyclic group which may be substituted with one C _1-8 alkyl group Or a pharmaceutically acceptable salt thereof.

[21] The heteroaromatic 5-membered ring compound or prodrug thereof according to [20] above, wherein the aromatic heterocycle according to [20] is a thiazolyl group, oxazolyl group, benzimidazolyl group, pyridyl group or quinolyl group Pharmaceutically acceptable salts of

[22] R ⁴ represents —CO—N (R ¹⁵ ) (R ¹⁶ ) (wherein R ¹⁵ represents a hydrogen atom, and R ¹⁶ represents an aryl group which may be substituted with one C _1-8 alkyl group) Or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[23] The heteroaromatic 5-membered ring compound or prodrug thereof according to any one of [1] to [22] selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof.
(1) 5- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid,
(2) 4- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -benzoic acid,
(3) 6- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid,
(4) 5- {4- [4-({Methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid,
(5) 4- {4- [4-({Methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -benzoic acid,
(6) 6- [4- (4-{[(4-Isopropyl-phenyl)-(1-propyl-butyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -nicotinic acid,
(7) 5- [4- (4-{[(4-Isopropyl-phenyl)-(1-propyl-butyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -nicotinic acid,
(8) 5- [4- (4-{[isobutyl- (4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -nicotinic acid,
(9) 4- [4- (4-{[(4-Isopropyl-phenyl)-(1-propyl-butyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -benzoic acid,
(10) 3- [4- (4-{[(4-Isopropyl-phenyl)-(1-propyl-butyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -benzoic acid,

(11) 6- [4- (4-{[(1-Ethyl-propyl)-(4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -nicotinic acid,
(12) 5- [4- (4-{[(1-Ethyl-propyl)-(4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -nicotinic acid,
(13) 4- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethylthio} -benzoic acid,
(14) 4- {4- [4-({Methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethylthio} -benzoic acid,
(15) 4- (Methyl- {4- [4-({methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -sulfamoyl) -benzoic acid,
(16) 4- (methyl- {4- [4-({methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -sulfamoyl) -Sodium butyrate,
(17) 4-{[(4- {4-[(4-cyclohexyl-phenylamino) -methyl] -phenyl} -thiazol-2-yl) -methyl-amino] -methyl} -benzoic acid,
(18) 4-({[4- (4-{[(4-Cyclohexyl-phenyl) -methyl-amino] -methyl} -phenyl) -thiazol-2-yl] -methyl-amino} -methyl) -benzoic acid acid,
(19) 4-[(methyl- {4- [4-({methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-yl} -amino ) -Methyl] -benzoic acid,
(20) 4-[({4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-yl} -methyl-amino ) -Methyl] -benzoic acid,

(21) (S)-({4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -methyl- Amino) -phenyl-acetic acid,
(22) (S) -2-({4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl}- Methyl-amino) -3-phenyl-propionic acid,
(23) {benzyl- [4- (4-{[(4-tert-butyl-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(24) {benzyl- [4- (4-{[(4-chloro-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(25) (Benzyl- {4- [4-({methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid ,
(26) (Benzyl- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid ,
(27) {1- [4- (4-{[(4-tert-Butyl-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl] -3-phenyl-ureido} -acetic acid ,
(28) {Benzoyl- [4- (4-{[(4-tert-butyl-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(29) [[4- (4-{[(4-tert-Butyl-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl]-(pyridin-2-ylcarbonyl) -amino ] -Acetic acid,
(30) [[4- (4-{[(4-tert-Butyl-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl]-(pyridin-3-ylcarbonyl) -amino ] -Acetic acid,

(31) {benzenesulfonyl- [4- (4-{[(4-tert-butyl-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(32) 2- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -1,2,3 , 4-tetrahydro-isoquinoline-3-carboxylic acid,
(33) (S) -2- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -1 , 2,3,4-tetrahydro-isoquinoline-3-carboxylic acid,
(34) (S) -2- {4- [4-({Methyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -1 , 2,3,4-tetrahydro-isoquinoline-3-carboxylic acid,
(35) (S) -2- [4- (4-{[(1-Ethyl-propyl)-(4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethyl] -1 , 2,3,4-tetrahydro-isoquinoline-3-carboxylic acid,
(36) 4-({4- [4- (4-cyclohexyl-phenoxymethyl) -phenyl] -thiazol-2-yl} -methyl-amino) -benzoic acid,
(37) 4-[({4- [4- (4-cyclohexyl-phenoxymethyl) -phenyl] -thiazol-2-yl} -methyl-amino) -methyl] -benzoic acid,
(38) 4-{[(4- {4- [4- (1,1-Dimethyl-propyl) -phenoxymethyl] -phenyl} -thiazol-2-yl) -methyl-amino] -methyl} -benzoic acid ,
(39) 4-{[Methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-yl) -amino] -methyl} -benzoic acid,
(40) 4-{[methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-yl) -amino] -methyl} -sodium benzoate,

(41) (S)-[methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -phenyl-acetic acid,
(42) (S) -2- [Methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -3-phenyl- Propionic acid,
(43) (Benzyl- {4- [4- (2-tert-butyl-4-methyl-phenoxymethyl) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(44) [Benzyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(45) 2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro-isoquinoline-3- carboxylic acid,
(46) (S) -2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro- Isoquinoline-3-carboxylic acid,
(47) (R) -2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro- Isoquinoline-3-carboxylic acid,
(48) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid,
(49) 4- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethoxy) -benzoic acid,
(50) 4- [methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -sulfamoyl] -benzoic acid,

(51) 4- [methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -sulfamoyl] -butyric acid,
(52) 4-({4- [4- (4-cyclohexyl-phenylcarbamoyl) -phenyl] -thiazol-2-yl} -methyl-amino) -benzoic acid,
(53) 4-[({4- [4- (4-cyclohexyl-phenylcarbamoyl) -phenyl] -thiazol-2-yl} -methyl-amino) -methyl] -benzoic acid,
(54) [Benzyl- (4- {4- [4- (1-propyl-butyl) -phenylcarbamoyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(55) [Benzyl- (4- {4- [4- (1-propyl-butyl) -benzylcarbamoyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(56) {benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -carbamoyl} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(57) {benzyl- [4- (4- {ethyl- [4- (1-propyl-butyl) -benzyl] -carbamoyl} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(58) 5- {4- [4-({(2-hydroxy-2-methyl-propyl)-[4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazole- 2-ylmethoxy} -nicotinic acid,
(59) [[4- (4-{[(4-tert-Butyl-phenyl) -isobutyl-amino] -methyl} -phenyl) -thiazol-2-ylmethyl]-(morpholine-4-carbonyl) -amino] -Acetic acid,
(60) 5- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -sodium nicotinate,

(61) (S) -2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro- Sodium isoquinoline-3-carboxylate,
(62) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethoxy) -sodium nicotinate,
(63) 3- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -5-methoxy-benzoic acid acid,
(64) (1- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-phenyl- (Ureido) -acetic acid,
(65) (1- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-p- (Tolyl-ureido) -acetic acid,
(66) [1- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3- (4 -Isopropyl-phenyl) -ureido] -acetic acid, (67) (1- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl]- Thiazol-2-ylmethyl} -3-methyl-3-phenyl-ureido) -acetic acid,
(68) 5- {4- [4-({Isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid,
(69) [3-Phenyl-1- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -ureido] -acetic acid,
(70) (3- (2,6-Dimethyl-phenyl) -1- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -Thiazol-2-ylmethyl} -ureido) -acetic acid,

(71) ({4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -phenylcarbamoylmethyl-amino) -Acetic acid,
(72) (1- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-isopropyl- (Ureido) -acetic acid,
(73) 3- {4- [4-({Isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -isoxazole-5-carvone acid,
(74) 5- [4- (4-{[(2-Ethyl-butyl)-(4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethoxy] -nicotinic acid,
(75) [{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-(piperidine-1-carbonyl ) -Amino] -acetic acid,
(76) 2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid,
(77) [{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-(p-tolylcarbamoyl- Methyl) -amino] -acetic acid,
(78) {{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-[(4-isopropyl- Phenylcarbamoyl) -methyl] -amino} -acetic acid,
(79) (1- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-methyl- 3-phenyl-ureido) -acetic acid,
(80) (1- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-p- (Tolyl-ureido) -acetic acid,

(81) ((2,3-Dihydro-indole-1-carbonyl)-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -Thiazol-2-ylmethyl} -amino) -acetic acid,
(82) 3- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethoxy) -pyridine-2-carboxylic acid,
(83) {[4- (4-{[(2-Ethyl-butyl)-(4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethyl] -phenylcarbamoylmethyl-amino} -Acetic acid,
(84) {[4- (4-{[(2-Ethyl-butyl)-(4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethyl]-[(4-isopropyl- Phenylcarbamoyl) -methyl] -amino} -acetic acid,
(85) 4- (2- {Carboxymethyl- [4- (4-{[(2-ethyl-butyl)-(4-isopropyl-phenyl) -amino] -methyl} -phenyl) -thiazol-2-ylmethyl ] -Amino} -acetylamino) -benzoic acid,
(86) 6- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethoxy) -pyridine-2-carboxylic acid,
(87) 5- {4- [4-({isobutyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid,
(88) (1- {4- [4-({isobutyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-phenyl- (Ureido) -acetic acid,
(89) 5- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid methyl ester,
(90) 4-Amino-3- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -benzoic acid acid,

(91) 3- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -benzoic acid,
(92) 3-({4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -amino) -benzoic acid acid,
(93) 3- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -4-nitro-benzoic acid acid,
(94) ((1H-benzimidazol-2-ylmethyl)-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazole- 2-ylmethyl} -amino) -acetic acid,
(95) [Phenylcarbamoylmethyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(96) [(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl)-(pyridin-3-ylcarbamoylmethyl) -amino] -acetic acid,
(97) [[(4-Dimethylamino-phenylcarbamoyl) -methyl]-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(98) [[(4-Methoxy-phenylcarbamoyl) -methyl]-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -Acetic acid,
(99) [[(Isopropyl-phenyl-carbamoyl) -methyl]-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino]- Acetic acid,
(100) [(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl)-(pyridin-2-ylcarbamoylmethyl) -amino] -acetic acid,

(101) [(2-oxo-2-pyrrolidin-1-yl-ethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -Amino] -acetic acid,
(102) [(4-Methyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino]- Acetic acid,
(103) 4- (3-cyclohexylmethyl-3- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazole-2- Ylmethyl} -ureido) -benzoic acid,
(104) 4- (3-Isobutyl-3- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl } -Ureido) -benzoic acid,
(105) (1- {4- [4-({isobutyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-methyl- 3-phenyl-ureido) -acetic acid,
(106) ({4- [4-({isobutyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -phenylcarbamoylmethyl-amino) -Acetic acid,
(107) {{4- [4-({Isobutyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-[(4-isopropyl- Phenylcarbamoyl) -methyl] -amino} -acetic acid,
(108) 4-acetylamino-3- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy}- benzoic acid,
(109) 4- (2-Dimethylamino-acetylamino) -3- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl]- Thiazol-2-ylmethoxy} -benzoic acid,
(110) ((1H-benzimidazol-2-ylmethyl)-{4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazole- 2-ylmethyl} -amino) -acetic acid,

(111) [(1H-Benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid ,
(112) 3- {4- [4-({Isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -4-methanesulfonylamino -benzoic acid,
(113) 4-Isobutyrylamino-3- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy }-benzoic acid,
(114) 4- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-oxo-3 , 4-Dihydro-2H-benzo [1,4] oxazine-6-carboxylic acid,
(115) 4- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -3-oxo-3 , 4-Dihydro-2H-benzo [1,4] oxazine-8-carboxylic acid,
(116) ({4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] thiazol-2-ylmethyl}-{methyl-phenyl-amino- Sulfonyl} -amino) -acetic acid,
(117) ([(4-Isopropyl-phenylcarbamoyl) -methyl]-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl]- Thiazol-2-ylmethyl} -amino) -acetic acid,
(118) ([(3,5-Dimethyl-phenylcarbamoyl) -methyl]-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl ] -Thiazol-2-ylmethyl} -amino) -acetic acid,
(119) ([(4-Dimethylamino-phenylcarbamoyl) -methyl]-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -Thiazol-2-ylmethyl} -amino) -acetic acid,
(120) ((Benzylcarbamoyl-methyl)-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -Amino) -acetic acid,

(121) [{4- [4-({Isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-[2- (morpholine- 4-yl) -2-oxo-ethyl] -amino] -acetic acid,
(122) [{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-(2-phenoxy-ethyl ) -Amino] -acetic acid,
(123) [{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-(2-phenylamino- Ethyl) -amino] -acetic acid,
(124) 2-Carboxymethoxy-5-({4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -Methyl-amino) -benzoic acid,
(125) 2-carboxymethoxy-5- [methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -benzoic acid,
(126) 3- {4- [4-({Isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -4- (2- Methylamino-acetylamino) -benzoic acid,
(127) [(4-tert-butyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(128) [phenyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(129) [(2-phenoxy-acetyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(130) [(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl)-(2-p-tolyloxy-acetyl) -amino] -acetic acid,

(131) (Ethoxycarbonylmethyl- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -amino) -Acetic acid dihydrochloride,
(132) ((4-tert-butyl-thiazol-2-ylmethyl)-{4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -Thiazol-2-ylmethyl} -amino) -acetic acid,
(133) 6- {4- [4-({Isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -pyridine-2-carboxylic acid acid,
(134) [(2-Benzyloxy-acetyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(135) [[2- (4-Isopropyl-phenoxy) -acetyl]-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(136) [(4,5-Dimethyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(137) 5- (4- {5- [4- (1-propyl-butyl) -phenoxymethyl] -thiophen-2-yl} -thiazol-2-ylmethoxy) -nicotinic acid,
(138) ((4-tert-butyl-thiazol-2-ylmethyl)-{4- [6-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -benzoxazole -2-yl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(139) ((1H-Benzimidazol-2-ylmethyl)-{4- [6-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -benzoxazole-2- Yl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(140) 5- {4- [6-({Isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -benzoxazol-2-yl] -thiazol-2-ylmethoxy}- Nicotinic acid,

(141) [(5-tert-Butyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(142) [{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-(2-oxo-2 -Piperidin-1-yl-ethyl) -amino] -acetic acid,
(143) 6- [methyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -pyridine-2-carboxylic acid,
(144) ({4- [6-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -benzoxazol-2-yl] -thiazol-2-ylmethyl} -amino ) -Acetic acid,
(145) (S)-(Carboxymethyl- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -Amino) -phenyl-acetic acid, (146) ((4,5-dimethyl-thiazol-2-ylmethyl)-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl]- Amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(147) [(5-tert-Butyl-oxazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(148) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl)- Amino] -acetic acid,
(149) (Isobutoxycarbonylmethyl- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -amino ) -Acetic acid dihydrochloride,
(150) ({4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -propoxycarbonylmethyl-amino) -Acetic acid dihydrochloride,

(151) 1- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -piperidine-4-carboxylic acid hydrochloride,
(152) 1- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -piperidine-4-carboxylic acid acid,
(153) 4- [4- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -piperazin-1-yl] -benzoic acid,
(154) 4- (4- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -piperazine- 1-yl) -benzoic acid,
(155) 2- [4- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -piperazin-1-yl] -benzoic acid,
(156) 3- [4- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -piperazin-1-yl] -benzoic acid,
(157) 4- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethoxy) -benzoic acid,
(158) 4- {4- [1- (4-Isopropyl-benzyl) -5- (1-propyl-butyl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethoxy} -benzoic acid,
(159) 4- {4- [1- (6-Methyl- (pyridin-2-ylmethyl))-5- (1-propyl-butyl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethoxy }-benzoic acid,
(160) 2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazole-
2-ylmethyl) -1,2,3,4-tetrahydro-isoquinoline-7-carboxylic acid,

(161) 4- [1- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -piperidin-4-yl] -benzoic acid,
(162) 3- [1- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -piperidin-4-yl] -benzoic acid,
(163) 6-[(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -carbamoyl] -nicotinic acid,
(164) 2- [1- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -piperidin-4-yl] -benzoic acid,
(165) 1- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethyl) -piperidine-4-carboxylic acid,
(166) 2- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro -Isoquinoline-7-carboxylic acid,
(167) 3-[(4- {1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethyl) -amino] -benzoic acid,
(168) 6-[(2-Amino-ethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -carbamoyl] -nicotinic acid Hydrochloride,
(169) 2- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-benzimidazol-2-yl} -thiazol-2-ylmethyl) -1,2,3,4- Tetrahydro-isoquinoline-7-carboxylic acid,
(170) 3- [4- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-benzimidazol-2-yl} -thiazol-2-ylmethyl) -piperazin-1-yl ]-benzoic acid,

(171) 4- [1- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-benzimidazol-2-yl} -thiazol-2-ylmethyl) -piperidin-4-yl ]-benzoic acid,
(172) 3- [4- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethyl) -piperazin-1-yl] -benzoic acid,
(173) 3- (1- {4- [4- (3,4-dichloro-benzyloxy) -phenyl] -thiazol-2-ylmethyl} -piperidin-4-yl) -benzoic acid,
(174) 3- (1- {4- [4- (3,5-bis-trifluoromethyl-benzyloxy) -phenyl] -thiazol-2-ylmethyl} -piperidin-4-yl) -benzoic acid,
(175) 3- (1- {4- [4- (4-butoxy-benzyloxy) -phenyl] -thiazol-2-ylmethyl} -piperidin-4-yl) -benzoic acid,
(176) 5-methyl-2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -2H-pyrazole-3-carboxylic acid,
(177) 5-methyl-1- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -1H-pyrazole-3-carboxylic acid,
(178) 5-tert-butyl-1- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -1H-pyrazole-3-carboxylic acid ,
(179) 5-tert-butyl-2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -2H-pyrazole-3-carboxylic acid ,
(180) (2S, 4R) -4-hydroxy-1- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethyl) -Pyrrolidine-2-carboxylic acid,

(181) 4- [4- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -piperidin-1-yl] -benzoic acid,
(182) 1- (4- {1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethyl) -1H-indole-3-carboxylic acid,
(183) 1- (4- {2-Phenyl-1- [4- (1-propyl-butyl) -benzyl] -1H-indol-3-yl} -thiazol-2-ylmethyl) -piperidine-4-carboxylic acid acid,
(184) 3- (1- {4- [4- (4-Methyl-3-nitro-benzyloxy) -phenyl] -thiazol-2-ylmethyl} -piperidin-4-yl) -benzoic acid,
(185) 2- {4- [1- (4-Isopropyl-benzyl) -6- (morpholin-4-yl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethyl} -1,2, 3,4-tetrahydro-isoquinoline-7-carboxylic acid,
(186) 3- (4- {4- [1- (4-Isopropyl-benzyl) -6- (morpholin-4-yl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethyl} -piperazine -1-yl) -benzoic acid,
(187) {benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -oxazol-2-ylmethyl] -amino} -acetic acid,
(188) 5- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid,
(189) 4- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -benzoic acid,
(190) 4- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethylthio) -benzoic acid,

(191) 4- {4- [4- (4-cyclohexyl-benzyloxy) -phenyl] -thiazol-2-ylmethylthio} -benzoic acid,
(192) 4- {4- [4- (4-cyclohexyl-benzyloxy) -phenyl] -thiazol-2-ylmethanesulfonyl} -benzoic acid,
(193) 4- [methyl- (4- {5-methyl-2- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -sulfamoyl] -benzoic acid,
(194) 4- [methyl- (4- {5-methyl-2- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -benzoic acid,
(195) (Benzyl- {4- [5-methyl-2- (4-trifluoromethyl-benzyloxy) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(196) [benzyl- (4- {5-methyl-2- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(197) [benzyl- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(198) [Benzyl- (4- {4- [4- (1-ethyl-propyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(199) (Benzyl- {4- [5-tert-butyl-2- (4-isobutyl-benzyloxy) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(200) [benzyl- (4- {5-chloro-2- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,

(201) [(4- {4- [4- (1-ethyl-propyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)-(4-fluoro-benzyl) -amino] -acetic acid,
(202) [(4- {4- [4- (1-ethyl-propyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)-(4-isopropyl-benzyl) -amino] -acetic acid,
(203) [(4- {4- [4- (1-Ethyl-propyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)-(4-trifluoromethyl-benzyl) -amino] -acetic acid,
(204) [(4-Chloro-benzyl)-(4- {4- [4- (1-ethyl-propyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(205) [(3,5-Dimethyl-benzyl)-(4- {4- [4- (1-ethyl-propyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(206) [(4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)-(pyridin-2-ylmethyl) -amino] -acetic acid,
(207) [(4- {4- [4- (1-Ethyl-propyl) -benzyloxy] -phenyl} -thiazole-2-
Ylmethyl)-(pyridin-2-ylmethyl) -amino] -acetic acid,
(208) [(4- {5-Methyl-2- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)-(pyridin-2-ylmethyl) -amino]- Acetic acid,
(209) [Benzoyl- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(210) [(4- {4- [4- (1-ethyl-propyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)-(4-methyl-benzoyl) -amino] -acetic acid,

(211) [(4-Methoxy-benzoyl)-(4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(212) 2- (4- {5-Methyl-2- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro- Isoquinoline-3-carboxylic acid,
(213) (S) -2- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro- Isoquinoline-3-carboxylic acid,
(214) {benzyl- [4- (4-{[4- (2,2-dimethyl-propyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(215) {Benzyl- [4- (4-{[trans-4- (4-tert-butyl-phenyl) -cyclohexylmethyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -amino}- Acetic acid,
(216) [Benzyl- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(217) 3- [benzyl- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -propionic acid,
(218) (Benzyl- {4- [4-({2- [4- (2,2-dimethyl-propyl) -phenyl] -ethyl} -methyl-amino) -phenyl] -thiazol-2-ylmethyl}- Amino) -acetic acid,
(219) {benzyl- [4- (4- {methyl- [4- (trans-4-methyl-cyclohexyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(220) {benzyl- [4- (4-{[4- (cis-4-fluoro-cyclohexyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,

(221) {benzyl- [4- (4-{[trans-4- (4-chloro-phenyl) -cyclohexylmethyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(222) {benzyl- [4- (4-{[4- (4,4-dimethyl-cyclohexyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(223) {benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(224) (Benzyl- {4- [4- (biphenyl-4-ylmethyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(225) [benzyl- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -sodium acetate,
(226) [benzyl- (4- {4-[(4-isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(227) {benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -sodium acetate,
(228) {benzyl- [4- (4-{[4- (2,2-dimethyl-propylthio) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(229) {benzyl- [4- (4- {methyl- [4- (3-methyl-butylthio) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(230) [Benzyl- (4- {4-[(4-dipropylamino-benzoyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,

(231) [(4- {4- [Ethyl- (4-isopropyl-benzyl) -amino] -phenyl} -thiazol-2-ylmethyl)-(4-isopropyl-benzyl) -amino] -acetic acid,
(232) [(4-Isopropyl-benzyl)-(4- {4- [isopropyl- (4-isopropyl-benzyl) -amino] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(233) [(4-tert-butyl-benzyl)-(4- {4- [isopropyl- (4-isopropyl-benzyl) -amino] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(234) [(4-Chloro-benzyl)-(4- {4-[(4-isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(235) {{4- [4- (Benzyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl}-[4- (1-propyl-butyl) -benzyl] -amino} -acetic acid,
(236) [{4- [4- (Benzyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl}-(4-chloro-benzyl) -amino] -acetic acid,
(237) [{4- [4- (Benzyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl}-(2-chloro-benzyl) -amino] -acetic acid,
(238) [{4- [4- (Benzyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl}-(3,4-dichloro-benzyl) -amino] -acetic acid,
(239) {[4- (4- {Methyl- [4- (trans-4-methyl-cyclohexyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl]-(pyridin-2-ylmethyl)- Amino} -acetic acid,
(240) {[4- (4- {Methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl]-(pyridin-2-ylmethyl) -amino} -Acetic acid,

(241) ({4- [4- (Benzyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl} -naphthalen-1-ylmethyl-amino) -acetic acid,
(242) ({4- [4- (Benzyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl} -quinolin-2-ylmethyl-amino) -acetic acid,
(243) ((2-Benzo [b] thiophen-3-yl-acetyl)-{4- [4- (benzyl-methyl-amino) -phenyl] -thiazol-2-ylmethyl} -amino) -acetic acid,
(244) [[2- (4-Chloro-phenyl) -acetyl]-(4- {4-[(4-isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -Acetic acid,
(245) {(4- {4-[(4-Isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl)-[2- (4-isopropyl-phenyl) -acetyl] -amino} -Acetic acid,
(246) [(4- {4-[(4-Isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl)-(3-methyl-butyryl) -amino] -acetic acid,
(247) {1- [4- (4-{[4- (2,2-Dimethyl-propyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -3-phenyl-ureido} -Acetic acid,
(248) [benzoyl- (4- {4-[(4-isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(249) {(4-Methyl-benzoyl)-[4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -Acetic acid,
(250) {(4-Isopropyl-benzoyl)-[4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -Sodium acetate,

(251) (S)-{3- [4- (4- {Methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-yl] -3,4- Dihydro-1H-isoquinolin-2-yl} -sodium acetate,
(252) 1- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -piperidine-4-carboxylic acid,
(253) 1- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -piperidine-3-carboxylic acid,
(254) 1- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -4-phenyl-piperidine-4-carboxylic acid,
(255) 1- (4- {4-[(4-Cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -4- (3-methyl-butyl) -piperidine-4-carboxylic acid acid,
(256) 1- [4- (4- {Methyl- [4- (trans-4-methyl-cyclohexyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -4-phenyl-piperidine-4 -carboxylic acid,
(257) 1- [4- (4-{[trans-4- (4-Chloro-phenyl) -cyclohexylmethyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -4-phenyl-piperidine- 4-carboxylic acid,
(258) 2- [4- (4- {Methyl- [4- (trans-4-methyl-cyclohexyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -1,2,3,4 -Tetrahydro-isoquinoline-3-carboxylic acid,
(259) 2- (4- {4-[(4-Isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro-isoquinoline-3-carbon acid,
(260) 2- [4- (4- {Methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -1,2,3,4-tetrahydro -Isoquinoline-3-carboxylic acid,

(261) 2- [4- (4-{[4- (2,2-Dimethyl-propyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -1,2,3,4 -Tetrahydro-isoquinoline-3-carboxylic acid,
(262) 5-{[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-yl) -methyl-amino] -methyl} -furan-2-carboxylic acid acid,
(263) 2-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -3-phenyl-propionic acid,
(264) [(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -phenyl-acetic acid,
(265) 2-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -propionic acid,
(266) 3- (4-Chloro-phenyl) -2-[(4- {4-[(4-isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -amino] -propion acid,
(267) [(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-amino] -acetic acid,
(268) 3-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-amino] -propionic acid,
(269) 4-{[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-amino] -methyl} -benzoic acid,
(270) 4-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-amino] -benzoic acid,

(271) 6-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-amino] -nicotinic acid,
(272) 2-[(4- {4-[(4-isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-amino] -3-phenyl-propionic acid,
(273) (S) -2- {Methyl- [4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -3-phenyl-propionic acid,
(274) (S)-{Methyl- [4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -phenyl -Acetic acid,
(275) {[4- (4-{[4- (2,2-Dimethyl-propyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -methyl-amino} -phenyl-acetic acid ,
(276) 2-{[4- (4-{[4- (2,2-dimethyl-propyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -methyl-amino} -3 -Phenyl-propionic acid,
(277) {carboxymethyl- [4- (4- {methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(278) [(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl)-(3-methyl-butyl) -amino] -acetic acid,
(279) {(3-Methyl-butyl)-[4- (4- {methyl- [4- (trans-4-methyl-cyclohexyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethyl]- Amino} -acetic acid,
(280) [(4- {4-[(4-isobutyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl)-(3-methyl-butyl) -amino] -acetic acid,

(281) 5- [4- (4- {Methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethoxy] -nicotinic acid,
(282) 4- [4- (4- {Methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethoxy] -benzoic acid,
(283) 4- [4- (4- {Methyl- [4- (1-propyl-butyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethylthio] -benzoic acid,
(284) 4-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -sulfamoyl] -benzoic acid,
(285) 4-{[4- (4-{[4- (4,4-Dimethyl-cyclohexyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -methyl-sulfamoyl} -benzoic acid acid,
(286) {[4- (4-{[4- (4,4-Dimethyl-cyclohexyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -methyl-sulfamoyl} -acetic acid,
(287) 4-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-sulfamoyl] -benzoic acid,
(288) 3-[(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-sulfamoyl] -benzoic acid,
(289) [(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -methyl-sulfamoyl] -acetic acid,
(290) 4-{[4- (4-{[4- (4,4-Dimethyl-cyclohexyl) -benzyl] -methyl-amino} -phenyl) -thiazol-2-ylmethyl] -methyl-sulfamoyl} -butyric acid ,

(291) [(4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -isobutyl-sulfamoyl] -acetic acid,
(292) N- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -oxamic acid,
(293) {benzyl- [4-({4- [4- (1-propyl-butyl) -benzyl] -methyl-aminocarbonyl} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(294) N- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -N-methyl-terephthalamic acid,
(295) {benzyl- [4- (4- {methyl- [4- (trans-4-methyl-cyclohexyl) -benzyl] -amino} -phenyl) -thiazol-2-ylmethoxycarbonyl] -amino} -acetic acid ,
(296) [3- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -3-methyl-ureido] -acetic acid,
(297) (cyclohexylmethyl- {4- [6- (3,4-dichloro-benzyloxy) -benzoxazol-2-yl] -thiazol-2-yl} -amino) -acetic acid,
(298) [4- (4- {4-[(4-cyclohexyl-benzyl) -methyl-amino] -phenyl} -thiazol-2-ylmethyl) -piperazin-1-yl] -acetic acid,
(299) (S) -2- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro- Sodium isoquinoline-3-carboxylate,

(300) 5- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid sodium salt,
(301) 5- (4- {2-Methyl-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid,
(302) 5- (4- {3-methoxy-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid,
(303) [(4- {2-Methyl-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -phenylcarbamoylmethyl-amino] -acetic acid,
(304) [[(4-Isopropyl-phenylcarbamoyl) -methyl]-(4- {2-methyl-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl ) -Amino] -acetic acid,
(305) 2- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro-isoquinoline-3- carboxylic acid,
(306) [(4- {3-methoxy-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -phenylcarbamoylmethyl-amino] -acetic acid,
(307) [[(4-Isopropyl-phenylcarbamoyl) -methyl]-(4- {3-methoxy-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl ) -Amino] -acetic acid,
(308) [(4- {2-methyl-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -thiazol-4-ylmethyl-amino] -acetic acid,
(309) [(4- {2-Methyl-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)-(2-methyl-thiazol-4-ylmethyl) -Amino] -acetic acid hydrochloride,
(310) [(Benzylcarbamoyl-methyl)-(4- {2-methyl-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -amino] -acetic acid Hydrochloride,

(311) [(1H-Benzimidazol-2-ylmethyl)-(4- {2-methyl-4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl)- Amino] -acetic acid,
(312) [(4-tert-Butyl-thiazol-2-ylmethyl)-(4- {1- [4- (1-propyl-butyl) -benzyl] -1,2,3,4-tetrahydro-quinoline- 6-yl} -thiazol-2-ylmethyl) -amino] -acetic acid,
(313) 1- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -piperidine-4-carboxylic acid hydrochloride,
(314) 4- [4- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethyl) -piperazin-1-yl] -benzoic acid,
(315) 4- {4- [5- (1-Ethyl-propyl) -1- (4-isopropyl-benzyl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethoxy} -benzoic acid ethyl ester ,
(316) 4- {4- [5- (1-ethyl-propyl) -1- (4-isopropyl-benzyl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethoxy} -benzoic acid,
(317) 4- {4- [1- (4-acetyl-benzyl) -5- (1-ethyl-propyl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethoxy} -benzoic acid,
(318) 4- {4- [1- (4-acetyl-benzyl) -6- (1-ethyl-propyl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethoxy} -benzoic acid,
(319) 4- {4- [1-cyclohexylmethyl-5- (1-ethyl-propyl) -1H-benzimidazol-2-yl] -thiazol-2-ylmethoxy} -benzoic acid,
(320) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid,

(321) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid,
(322) 5- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiophen-2-ylmethoxy} -nicotinic acid,
(323) 5- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethoxy} -nicotinic acid,
(324) 5- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophene-
2-ylmethoxy) -nicotinic acid,
(325) [(1H-Benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid ,
(326) 6- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -pyridine-2-carboxylic acid,
(327) [(1H-Benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid ,
(328) [[(4-Isopropyl-phenylcarbamoyl) -methyl]-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -Acetic acid,
(329) [phenylcarbamoylmethyl- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(330) ({4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl} -phenylcarbamoylmethyl-amino) -Acetic acid,

(331) ((4-tert-butyl-thiazol-2-ylmethyl)-{4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -Thiophen-2-ylmethyl} -amino) -acetic acid,
(332) [(5-tert-Butyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(333) ((1H-benzimidazol-2-ylmethyl)-{4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophene- 2-ylmethyl} -amino) -acetic acid,
(334) [(4-tert-Butyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(335) [Phenylcarbamoylmethyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(336) 5- {5- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethoxy} -nicotinic acid,
(337) 5- {5- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiophen-2-ylmethoxy} -nicotinic acid,
(338) ((4-tert-butyl-thiazol-2-ylmethyl)-{5- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -Thiophen-2-ylmethyl} -amino) -acetic acid,
(339) ((4-tert-butyl-thiazol-2-ylmethyl)-{5- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -Thiophen-2-ylmethyl} -amino) -acetic acid,
(340) ((1H-benzimidazol-2-ylmethyl)-{5- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophene- 2-ylmethyl} -amino) -acetic acid,

(341) ((1H-benzimidazol-2-ylmethyl)-{5- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiophene- 2-ylmethyl} -amino) -acetic acid,
(342) [(4,5-Dimethyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(343) (S) -2- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl} -1 , 2,3,4-tetrahydro-isoquinoline-3-carboxylic acid,
(344) {{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl}-[(4-isopropyl- Phenylcarbamoyl) -methyl] -amino} -acetic acid,
(345) (S) -2- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -1,2,3,4-tetrahydro- Isoquinoline-3-carboxylic acid,
(346) [[(4-Isopropyl-phenylcarbamoyl) -methyl]-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -Acetic acid,
(347) (S) -2- {5- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl} -1 , 2,3,4-tetrahydro-isoquinoline-3-carboxylic acid,
(348) [(5-tert-Butyl-oxazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(349) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid,
(350) 6- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -pyridine-2-carboxylic acid,

(351) 6- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethoxy} -pyridine-2-carboxylic acid acid,
(352) ((5-tert-butyl-thiazol-2-ylmethyl)-{4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -Thiophen-2-ylmethyl} -amino) -acetic acid,
(353) [{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl}-(1-methyl-1H -Benzimidazol-2-ylmethyl) -amino] -acetic acid,
(354) [(4-tert-butyl-thiazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(355) [{5- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl}-(1-methyl-1H -Benzimidazol-2-ylmethyl) -amino] -acetic acid,
(356) [(5-tert-butyl-thiazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(357) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -sodium acetate,
(358) Bis {[(1-Methyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl ) -Amino] -acetic acid} calcium,
(359) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid toluene-4-sulfonate,
(360) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid sulfate,

(361) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl)- Amino] -acetic acid,
(362) [(5-tert-Butyl-thiazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl) -amino ] -Acetic acid,
(363) [(4-Isopropyl-benzyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl) -amino] -acetic acid,
(364) [(4-Dimethylamino-benzyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl) -amino] -acetic acid,
(365) [(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl)-(pyridin-2-ylmethyl) -amino] -acetic acid,
(366) [(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl) -pyridin-3-ylmethyl-amino] -acetic acid,
(367) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid methanesulfonate,
(368) [Methanesulfonyl- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(369) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -sodium nicotinate,
(370) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid hydrochloride,

(371) 4- [4- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl) -piperazin-1-yl] -benzoic acid,
(372) 4- [1- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-carbonyl) -piperidin-4-yl] -benzoic acid,
(373) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid hydrochloride,
(374) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid sulfate,
(375) 4- (2-Dimethylamino-acetylamino) -3- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -benzoic acid ,
(376) 4-isobutyrylamino-3- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -benzoic acid,
(377) 4- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -benzoic acid,
(378) 4- (Methanesulfonyl-methyl-amino) -3- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -benzoic acid,
(379) 4- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethylthio) -benzoic acid,
(380) 4-amino-3- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -benzoic acid,

(381) 1- {5- [1- (4-cyclohexyl-benzyl) -1H-indol-3-yl] -thiophen-2-ylmethyl} -4-phenyl-piperidine-4-carboxylic acid hydrochloride,
(382) (Benzyl- {5- [1- (4-cyclohexyl-benzyl) -1H-indol-3-yl] -thiophen-2-ylmethyl} -amino) -acetic acid hydrochloride,
(383) [(Methyl-phenyl-sulfamoyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(384) [(5-tert-butyl-thiazol-2-ylmethyl)-(5- {4-[(4-cyclohexyl-phenyl) -methyl-carbamoyl] -phenyl} -thiophen-2-ylmethyl) -amino] -Acetic acid,
(385) [(5- {4-[(4-cyclohexyl-benzyl) -ethyl-amino] -phenyl} -thiophen-2-ylmethyl)-(pyridin-2-ylmethyl) -amino] -acetic acid,
(386) [(5- {4-[(4-cyclohexyl-benzyl) -ethyl-amino] -phenyl} -thiophen-2-ylmethyl)-(2-phenoxy-ethyl) -amino] -acetic acid,
(387) 4- {1- [4- (4-{[trans-4- (4-tert-Butyl-phenyl) -cyclohexylmethyl] -ethyl-amino} -phenyl) -thiophen-2-ylmethyl] -piperidine -4-yl} -benzoic acid,
(388) [[2- (4-Isopropyl-phenoxy) -acetyl]-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(389) [(4-Isopropyl-benzoyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(390) [(3-Methyl-butyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,

(391) [3-Methyl-3-phenyl-1- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -ureido] -acetic acid,
(392) 2- (4- {3- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -1,2,3,4-tetrahydro-isoquinoline-7- carboxylic acid,
(393) 4- [4- (5- {4- [4- (trans-4-methyl-cyclohexyl) -benzyloxy] -phenyl} -thiophen-2-ylmethyl) -piperazin-1-yl] -benzoic acid ,
(394) [(2-Chloro-5-trifluoromethyl-benzyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(395) 3-{[carboxymethyl- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -methyl} -benzoic acid,
(396) [(4-Methoxy-benzyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(397) [(4-Methylthio-benzyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(398) 4- [cyclohexylmethyl- (5- {4- [4- (trans-4-methyl-cyclohexyl) -benzyloxy] -phenyl} -thiophen-2-ylmethyl) -sulfamoyl] -benzoic acid,
(399) 4- [3-cyclohexylmethyl-3- (5- {4- [4- (trans-4-methyl-cyclohexyl) -benzyloxy] -phenyl} -thiophen-2-ylmethyl) -ureido] -benzoic acid acid,
(400) [Benzhydryl- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,

(401) [[2-Oxo-2- (4-pyrrolidin-1-yl-phenyl) -ethyl]-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl}- Thiophen-2-ylmethyl) -amino] -acetic acid ethyl ester hydrochloride,
(402) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid ethyl ester,
(403) 3- (Benzyl- {5- [1- (4-cyclohexyl-benzyl) -2,3-dihydro-1H-indol-5-yl] -thiophen-2-ylmethyl} -amino) -propionic acid,
(404) [Benzyl- (4- {4- [2- (2,2-dimethyl-propyl) -benzimidazol-1-ylmethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(405) [(1-Methyl-1H-indol-3-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(406) [(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -quinolin-2-ylmethyl-amino] -acetic acid,
(407) [Benzothiazol-2-ylmethyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(408) [(1-Benzyl-1H-imidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(409) [(1H-Indol-5-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(410) [(4-Imidazol-1-yl-benzyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino]- Acetic acid,

(411) [Benzofuran-2-ylmethyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(412) [[2,2 '] bithiophenyl-5-ylmethyl- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino]- Acetic acid,
(413) [(2-Phenyl-1H-imidazol-4-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(414) [(3-Phenyl-1H-pyrazol-4-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(415) [Benzoxazol-2-ylmethyl- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(416) [Benzo [b] thiophen-2-ylmethyl- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(417) [(4-Phenyl-thiophen-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino]- Acetic acid,
(418) [Benzothiazol-2-yl- (5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(419) [(5-Chloro-thiophen-2-sulfonyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino]- Acetic acid,
(420) [(1-Diethylcarbamoylmethyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl ) -Amino] -acetic acid,

(421) (S)-({4- [2- (4-cyclohexyl-benzyloxy) -5-methyl-phenyl] -thiophen-2-ylmethyl} -methyl-amino) -3-phenyl-propionic acid,
(422) [Benzyl- (4- {4-[(4-butoxy-benzenesulfonyl) -ethyl-amino] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid,
(423) N- {4- [2- (4-cyclohexyl-benzyloxy) -5-methyl-phenyl] -thiophen-2-ylmethyl} -N- (2-methyl-benzothiazol-6-yl) -oxamide acid,
(424) (benzyl- {4- [4- (3,5-dichloro-phenoxymethyl) -phenyl] -thiophen-2-ylmethyl} -amino) -acetic acid,
(425) [(1-Allyl-1H-benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid and (426) [[4- (4-chloro-phenyl) -thiazol-2-yl]-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -Thiophen-2-ylmethyl) -amino] -acetic acid.

[24] The heteroaromatic 5-membered ring compound or prodrug thereof according to any one of [1] to [23] selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof.
(1) (S) -2- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -1,2,3,4-tetrahydro- Isoquinoline-3-carboxylic acid,
(2) {{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethyl}-[(4-isopropyl- Phenylcarbamoyl) -methyl] -amino} -acetic acid,
(3) 4- (3-Isobutyl-3- {4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl } -Ureido) -benzoic acid,
(4) ({4- [4-({isobutyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl] -thiazol-2-ylmethyl} -phenylcarbamoylmethyl-amino) -Acetic acid,
(5) ([(4-Isopropyl-phenylcarbamoyl) -methyl]-{4- [4-({isopropyl- [4- (1-propyl-butyl) -phenyl] -amino} -methyl) -phenyl]- Thiazol-2-ylmethyl} -amino) -acetic acid,
(6) [(4-tert-Butyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(7) [(4,5-Dimethyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(8) [(5-tert-Butyl-thiazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino ] -Acetic acid,
(9) [[2- (4-Isopropyl-phenoxy) acetyl]-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -amino] -Acetic acid,
(10) 4- [4- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiazol-2-ylmethyl) -piperazin-1-yl] -benzoic acid,

(11) {benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) benzyl] amino} -phenyl) -thiazol-2-ylmethyl] -amino} -acetic acid,
(12) [(1-Methyl-1H-benzimidazol-2-ylmethyl) -5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino ] -Acetic acid,
(13) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy} -nicotinic acid,
(14) [(1H-Benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid ,
(15) [(1H-Benzimidazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -acetic acid ,
(16) [[(4-Isopropyl-phenylcarbamoyl) -methyl]-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl) -amino] -Acetic acid,
(17) (S) -2- {4- [4-({[4- (1-ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl} -1 , 2,3,4-tetrahydro-isoquinoline-3-carboxylic acid,
(18) {{4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiophen-2-ylmethyl}-[(4-isopropyl- Phenylcarbamoyl) -methyl] -amino} -acetic acid,
(19) [(1-Methyl-1H-benzimidazol-2-ylmethyl)-(4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl)- Amino] -acetic acid and (20) [(4-tert-butyl-thiazol-2-ylmethyl)-(5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophene-2 -Ylmethyl) -amino] -acetic acid.

[25] A pharmaceutical composition comprising the heteroaromatic 5-membered ring compound or prodrug thereof according to any one of [1] to [24] above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Stuff.

[26] Receptor type containing the heteroaromatic 5-membered ring compound or prodrug thereof according to any one of [1] to [24] above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for inhibiting a tyrosine kinase negative regulator.

[27] A protein tyrosine containing the heteroaromatic 5-membered ring compound or prodrug thereof according to any one of [1] to [24] above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for inhibiting phosphatase 1B.

[28] Diabetes prevention comprising the heteroaromatic 5-membered ring compound according to any one of [1] to [24] above or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Or a therapeutic pharmaceutical composition.

[29] High fat containing the heteroaromatic 5-membered ring compound or prodrug thereof according to any one of [1] to [24] above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for preventing or treating septicemia.

[30] Obesity containing the heteroaromatic 5-membered ring compound or prodrug thereof according to any one of [1] to [24] above, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for prevention or treatment.

[31] A diabetic complication comprising the heteroaromatic 5-membered ring compound according to any one of [1] to [24] above or a prodrug thereof, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A pharmaceutical composition for preventing or treating infectious diseases.

[32] The pharmaceutical composition according to the above [25], which is used in combination with a therapeutic drug for hyperlipidemia.

[33] Antihyperlipidemic drugs are HMG-CoA reductase inhibitor (statin), fibrate, TNFSF6 expression inhibitor, HDL-cholesterol increase agent, apoA1 expression enhancer, SPP1 (osteopontin) expression inhibitor, peroxisome proliferation Agents that act on factor-activated receptors (PPARs), PPARα agonists, lipase clarifier stimulants, cholesterol antagonists, platelet anticoagulants, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor upregulators, The pharmaceutical composition of the above-mentioned [32], which is one or more drugs selected from the group consisting of bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acid.

[34] Antihyperlipidemic drugs are lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostatin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (simvinolin), pitavastatin (italavastatin, nisvastatin) calcium, Lonifibrate (Lonifibrate), Vinifibrate (Vinifibrate), Clinofibrate, Cyprofibrate, Clofibrate, Etofibrate, Fenofibrate, Bezafibrate, Gemfibrozil, Acipimox, Eicosapentaenoic acid (icosapentate, icopenate, icosapentate) , Probucol, policosanol, colesevelam hydrochloride, cholestyramine (cholestyramine resin), cohydrochloride The pharmaceutical composition according to the above [33], which is one or more drugs selected from the group consisting of restipol, colestimide (cholestilan), ezetimibe and niacin (nicotinic acid).

[35] The pharmaceutical composition according to the above [25], which is used in combination with a therapeutic agent for diabetes.

[36] The therapeutic agent for diabetes is an insulin secretagogue, biguanide, α-glucosidase inhibitor, insulin preparation, insulin analog, insulin sensitivity enhancer, IL-11, anti-CD25 (IL-2 receptor) agent, angiotensin ( AT1) antagonist, angiotensin converting enzyme (ACE) inhibitor, aldose reductase inhibitor, antioxidant, carnitine acetyltransferase stimulant, antidepressant, glucocorticoid, retilin, radical formation agonist and transketolase activator The pharmaceutical composition of the above-mentioned [35], which is one or more drugs selected from the group.

[37] Antidiabetic drugs include nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybsol, glipizide, gluconeuride, glyquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epalrest Miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate / biotin, V-411, recombinant human interleukin-11, dasiliximab (dacilitumab), losartan potassium, captopril, imidapril hydrochloride, α-lipoic acid, lebasecarnin hydrochloride (Acetyl-L-carnitine, acetyl levocarnitine), captopril, retilin, verteporfin, benfotiamine and fluocinolone Is one or more agents selected from the group consisting of Tonido above [36] The pharmaceutical composition according.

[38] The pharmaceutical composition according to the above [25], which is used in combination with a therapeutic agent for obesity.

[39] A therapeutic agent for obesity is mazindol, a lipase inhibitor, a 5-HT / norepinephrine reuptake dual inhibitor, a 5-HT reuptake inhibitor, a supplement containing herbal ephedrine and caffeine, human chorionic gonadotropin, adrenaline The pharmaceutical composition of the above-mentioned [38], which is one or more drugs selected from the group consisting of a receptor agonist, methamphetamine, fentamine and amfepramon.

[40] Anti-obesity drugs include mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using the NCP system, metallaminol, d-methamphetamine hydrochloride, phentermine, The pharmaceutical composition of the above-mentioned [39], which is one or more drugs selected from the group consisting of amfepramon hydrochloride (diethylpropion), benzphetamine hydrochloride, and phendimetrazine tartrate.

[41] The pharmaceutical composition according to the above [25], which is used in combination with a therapeutic agent for hypertension.

[42] Antihypertensive drugs are thiazide, aldosterone antagonist, adrenergic neuron blocker, calcium channel blocker, dopamine D2 antagonist, β-adrenergic receptor antagonist, α2-adrenergic receptor agonist, guanylic acid Cyclase activator, β1-adrenergic receptor antagonist, α1-adrenergic receptor antagonist, antioxidant, angiotensin-I converting enzyme (ACE) inhibitor, Na ⁺ / H ⁺ exchange inhibitor, α-adrenergic receptor Antagonist, nitric oxide donor, 5-HT2 antagonist, K (ATP) channel activator, potassium-retaining diuretic prostaglandin synthase stimulator, imidazoline I1 receptor agonist, angiotensin AT1 antagonist, dopamine D1 agonist Agent, guanylate cyclase stimulant, endothelin ETA receptor antagonist, endothelin ETB receptor antagonist, NOS3 expression enhancer, prostasai Kulin analog, prostaglandin, angiotensin II antagonist, electrolyte absorption agonist, nicotine antagonist, dopamine D2 agonist, prolactin inhibitor, platelet activating factor (PAF) antagonist, platelet coagulation antagonist, tumor necrosis factor antagonist [41] above, which is one or more drugs selected from the group consisting of: a Rho kinase inhibitor, a PPARα agonist, an AMPA receptor modulator, a GABA (A) receptor antagonist, and a phosphodiesterase V (PDE5A) inhibitor. Pharmaceutical composition.

[43] Antihypertensive drugs are chlorothiazide, hydrochlorothiazide, hydroflumethiazide, meticlotiazide, polythiazide, cypamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxy mexrenone (eprerenone), mono Guanetidine sulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tartatrol hydrochloride , Seriprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, chloranolol hydrochloride, bevantol hydrochloride ( ), Clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine, nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, furanidipine hydrochloride (manidipine), rasidipine, isradipine, valnidipine hydrochloride (methapidipine hydrochloride, ethanol) , Sinaldipine (silnidipine), alanidipine, lercanidipine hydrochloride (masnidipine), azelnidipine, amlodipine, manidipine (furanidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol rollol, cartrolol hydrochloride , Prazosin hydrochloride, urapidil, hydrochloric acid Nandamine, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinoprilate, fosinoprilate , Trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilate, zofenoprilate, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradrol), phosphosidemine, ketanserin, pinacidil, cicletanide (cicletanide) Amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, meso Eprosartan formate, candesartan cilexetil (hexetyl), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesylate, cadralazine, rilmenidine dihydrogen phosphate, bosentan, beraprost sodium, limaprost alphadex (α-cyclodextrin), uniprost (tredextrin) (Prostinyl sodium), iloprost (cyloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, chlorichromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlorthalidone, kinetazone, indapamide, metolazone, phenoxybenzamine hydrochloride, , Diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, resell The pharmaceutical composition of the above-mentioned [42], which is one or more drugs selected from the group consisting of pin and methyldopa.

[44] The pharmaceutical composition according to the above [25], which is used in combination with a therapeutic agent for thrombosis.

[45] The therapeutic agent for thrombosis is one or more drugs selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, antithrombin preparations, antiplatelet agents and thrombolytic agents. A pharmaceutical composition according to [44] above.

[46] The therapeutic agent for thrombosis is heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, leviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human antithrombin III , Aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, ozagrel sodium, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasarplase, nateplase, monteplase, pamiteplase, batroxobin C, and citric acid C The above [45], which is one or more drugs selected from the group Pharmaceutical composition.

[47] The pharmaceutical composition for preventing or treating diabetes according to [28], which is used in combination with a therapeutic drug for hyperlipidemia.

[48] Antihyperlipidemic drugs are HMG-CoA reductase inhibitor (statin), fibrate, TNFSF6 expression inhibitor, HDL-cholesterol increase agent, apoA1 expression enhancer, SPP1 (osteopontin) expression inhibitor, peroxisome proliferation Agents that act on factor-activated receptors (PPARs), PPARα agonists, lipase clarifier stimulants, cholesterol antagonists, platelet anticoagulants, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor upregulators, The pharmaceutical composition for preventing or treating diabetes according to the above [47], which is one or more drugs selected from the group consisting of bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acid.

[49] Antihyperlipidemic drugs are lovastatin, pravastatin (eptatinatin) sodium, fluvastatin (fluindostatin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (simvinolin), pitavastatin (italavastatin, nisvastatin) calcium, Lonifibrate (Lonifibrate), Vinifibrate (Vinifibrate), Clinofibrate, Cyprofibrate, Clofibrate, Etofibrate, Fenofibrate, Bezafibrate, Gemfibrozil, Acipimox, Eicosapentaenoic acid (icosapentate, icopenate, icosapentate) , Probucol, policosanol, colesevelam hydrochloride, cholestyramine (cholestyramine resin), cohydrochloride The pharmaceutical composition for preventing or treating diabetes according to the above [48], which is one or more drugs selected from the group consisting of restipol, colestimide (cholestilan), ezetimibe and niacin (nicotinic acid).

[50] The pharmaceutical composition for preventing or treating diabetes according to [28], which is used in combination with another therapeutic agent for diabetes.

[51] Other therapeutic agents for diabetes include insulin secretagogues, biguanides, α-glucosidase inhibitors, insulin preparations, insulin analogs, insulin sensitivity enhancers, IL-11, anti-CD25 (IL-2 receptor) agents, Angiotensin (AT1) antagonist, angiotensin converting enzyme (ACE) inhibitor, aldose reductase inhibitor, antioxidant, carnitine acetyltransferase stimulator, antidepressant, glucocorticoid, retilin, radical formation agonist and transketolase activator The pharmaceutical composition for preventing or treating diabetes according to [50] above, which is one or more drugs selected from the group consisting of:

[52] Other anti-diabetic drugs are nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybazole, glipizide, gurbornuride, glyquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, Epalrestat, miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate / biotin, V-411, recombinant human interleukin-11, dasiliximab (dacilizumab), losartan potassium, captopril, imidapril hydrochloride, α-lipoic acid, Lebasecarnin hydrochloride (acetyl-L-carnitine, acetyl levocarnitine), captopril, retilin, verteporfin, benfotiamine and fluocinolone The pharmaceutical composition for preventing or treating diabetes according to the above [51], which is one or more drugs selected from the group consisting of acetonides.

[53] The pharmaceutical composition for preventing or treating diabetes according to the above [28], which is used in combination with a therapeutic agent for obesity.

[54] A therapeutic agent for obesity is mazindol, a lipase inhibitor, a 5-HT / norepinephrine reuptake dual inhibitor, a 5-HT reuptake inhibitor, a supplement containing herbal ephedrine and caffeine, human chorionic gonadotropin, adrenaline The pharmaceutical composition for preventing or treating diabetes according to the above [53], which is one or more drugs selected from the group consisting of a receptor agonist, methamphetamine, fentamine and amfepramon.

[55] Anti-obesity drugs include mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using the NCP system, metallaminol, d-methamphetamine hydrochloride, phentermine, The pharmaceutical composition for preventing or treating diabetes according to the above [54], which is one or more drugs selected from the group consisting of amfepramon hydrochloride (diethylpropion), benzphetamine hydrochloride, and phendimetrazine tartrate.

[56] The pharmaceutical composition for preventing or treating diabetes according to [28], which is used in combination with a therapeutic agent for hypertension.

[57] Antihypertensive drugs are thiazide, aldosterone antagonist, adrenergic neuron blocker, calcium channel blocker, dopamine D2 antagonist, β-adrenergic receptor antagonist, α2-adrenergic receptor agonist, guanylic acid Cyclase activator, β1-adrenergic receptor antagonist, α1-adrenergic receptor antagonist, antioxidant, angiotensin-I converting enzyme (ACE) inhibitor, Na ⁺ / H ⁺ exchange inhibitor, α-adrenergic receptor Antagonist, nitric oxide donor, 5-HT2 antagonist, K (ATP) channel activator, potassium-retaining diuretic prostaglandin synthase stimulator, imidazoline I1 receptor agonist, angiotensin AT1 antagonist, dopamine D1 agonist Agent, guanylate cyclase stimulant, endothelin ETA receptor antagonist, endothelin ETB receptor antagonist, NOS3 expression enhancer, prostasai Kulin analog, prostaglandin, angiotensin II antagonist, electrolyte absorption agonist, nicotine antagonist, dopamine D2 agonist, prolactin inhibitor, platelet activating factor (PAF) antagonist, platelet coagulation antagonist, tumor necrosis factor antagonist [56] above, which is one or more drugs selected from the group consisting of: a Rho kinase inhibitor, a PPARα agonist, an AMPA receptor modulator, a GABA (A) receptor antagonist, and a phosphodiesterase V (PDE5A) inhibitor. A pharmaceutical composition for preventing or treating diabetes.

[58] Antihypertensive drugs include chlorothiazide, hydrochlorothiazide, hydroflumethiazide, meticlotiazide, polythiazide, cypamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxy mexrenone (eprerenone), mono Guanetidine sulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tartatrol hydrochloride , Seriprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, chloranolol hydrochloride, bevantol hydrochloride (beba ), Clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine, nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, furanidipine hydrochloride (manidipine), rasidipine, isradipine, valnidipine hydrochloride (methapidipine hydrochloride, ethanol) , Sinaldipine (silnidipine), alanidipine, lercanidipine hydrochloride (masnidipine), azelnidipine, amlodipine, manidipine (furanidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol rollol, cartrolol hydrochloride , Prazosin hydrochloride, urapidil, hydrochloric acid a Nandamine, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinoprilate, fosinoprilate , Trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilate, zofenoprilate, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradrol), phosphosidemine, ketanserin, pinacidil, cicletanide (cicletanide) Amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, mesi Eprosartan acid, candesartan cilexetil (hexetyl), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesylate, cadralazine, rilmenidine dihydrogen phosphate, bosentan, beraprost sodium, limaprost alphadex (α-cyclodextrin), uniprost (treprodextrin) Stynyl sodium), iloprost (cyloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, chlorichromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlorthalidone, quinetazone, indapamide, metolazone, phenoxybenzamine hydrochloride, tyrosine Diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, resell Is one or more agents selected from the group consisting of down and methyldopa above [57] Diabetes Prevention or therapeutic pharmaceutical composition.

[59] The pharmaceutical composition for preventing or treating diabetes according to the above [28], which is used in combination with a therapeutic agent for thrombosis.

[60] The therapeutic agent for thrombosis is one or more drugs selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, antithrombin preparations, antiplatelet agents and thrombolytic agents. A pharmaceutical composition for preventing or treating diabetes according to [59] above.

[61] The therapeutic agent for thrombosis is heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, leviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human antithrombin III , Aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, ozagrel sodium, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasarplase, nateplase, monteplase, pamiteplase, batroxobin C, and citric acid C [60] The description above, which is one or more drugs selected from the group Diabetes Prevention or therapeutic pharmaceutical composition.

[62] The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [29], which is used in combination with another therapeutic drug for hyperlipidemia.

[63] Other therapeutic agents for hyperlipidemia are HMG-CoA reductase inhibitor (statin), fibrate, TNFSF6 expression inhibitor, HDL-cholesterol increase agent, apoA1 expression enhancer, SPP1 (osteopontin) expression inhibitor, Drugs that act on peroxisome proliferator-activated receptor (PPAR), PPARα agonists, lipase clarifier stimulants, cholesterol antagonists, platelet coagulation antagonists, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor up The pharmaceutical composition for prevention or treatment of hyperlipidemia according to the above [62], which is one or more drugs selected from the group consisting of regulators, bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acid.

[64] Other antihyperlipidemic drugs are lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostatinin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (simvinolin), pitavastatin (itavastatin, nisvastatin) Calcium, lonifibrate (lonifibrate), binifibrate (vinifibrate), clinofibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, bezafibrate, genfibrozil, acipimox, eicosapentaenoic acid (icosapentate, icopenate), icosapentate Ethyl ester, probucol, policosanol, colesevelam hydrochloride, cholestyramine (cholestyramine resin), salt The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [63], which is one or more drugs selected from the group consisting of acid colestipol, colestimide (cholestilan), ezetimibe and niacin (nicotinic acid).

[65] The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [29], which is used in combination with a therapeutic agent for diabetes.

[66] The therapeutic agent for diabetes is an insulin secretagogue, biguanide, α-glucosidase inhibitor, insulin preparation, insulin analog, insulin sensitivity enhancer, IL-11, anti-CD25 (IL-2 receptor) agent, angiotensin ( AT1) antagonist, angiotensin converting enzyme (ACE) inhibitor, aldose reductase inhibitor, antioxidant, carnitine acetyltransferase stimulant, antidepressant, glucocorticoid, retilin, radical formation agonist and transketolase activator The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [65], which is one or more drugs selected from the group.

[67] Antidiabetic drugs include nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybazole, glipizide, gluconeuride, glyquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epallet Miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate / biotin, V-411, recombinant human interleukin-11, dasiliximab (dacilitumab), losartan potassium, captopril, imidapril hydrochloride, α-lipoic acid, lebasecarnin hydrochloride (Acetyl-L-carnitine, acetyl levocarnitine), captopril, retilin, verteporfin, benfotiamine and fluocinolone Is one or more agents selected from the group consisting of Tonido above [66] hyperlipidemia preventive or therapeutic pharmaceutical composition.

[68] The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [29], which is used in combination with a therapeutic agent for obesity.

[69] A therapeutic agent for obesity is mazindol, a lipase inhibitor, a 5-HT / norepinephrine reuptake dual inhibitor, a 5-HT reuptake inhibitor, a supplement containing herbal ephedrine and caffeine, human chorionic gonadotropin, adrenaline The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [68], which is one or more drugs selected from the group consisting of a receptor agonist, methamphetamine, fentamine and amfepramon.

[70] Anti-obesity drugs include mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using the NCP system, metallaminol, d-methamphetamine hydrochloride, phentermine, The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [69], which is one or more drugs selected from the group consisting of amfepramon hydrochloride (diethylpropion), benzphetamine hydrochloride, and phendimetrazine tartrate.

[71] The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [29], which is used in combination with a drug for treating hypertension.

[72] Antihypertensive drugs are thiazide, aldosterone antagonist, adrenergic neuron blocker, calcium channel blocker, dopamine D2 antagonist, β-adrenergic receptor antagonist, α2-adrenergic receptor agonist, guanylic acid Cyclase activator, β1-adrenergic receptor antagonist, α1-adrenergic receptor antagonist, antioxidant, angiotensin-I converting enzyme (ACE) inhibitor, Na ⁺ / H ⁺ exchange inhibitor, α-adrenergic receptor Antagonist, nitric oxide donor, 5-HT2 antagonist, K (ATP) channel activator, potassium-retaining diuretic prostaglandin synthase stimulator, imidazoline I1 receptor agonist, angiotensin AT1 antagonist, dopamine D1 agonist Agent, guanylate cyclase stimulant, endothelin ETA receptor antagonist, endothelin ETB receptor antagonist, NOS3 expression enhancer, prostasai Kulin analog, prostaglandin, angiotensin II antagonist, electrolyte absorption agonist, nicotine antagonist, dopamine D2 agonist, prolactin inhibitor, platelet activating factor (PAF) antagonist, platelet coagulation antagonist, tumor necrosis factor antagonist [71] The above [71], which is one or more drugs selected from the group consisting of: a Rho kinase inhibitor, a PPARα agonist, an AMPA receptor modulator, a GABA (A) receptor antagonist, and a phosphodiesterase V (PDE5A) inhibitor. A pharmaceutical composition for preventing or treating hyperlipidemia.

[73] Antihypertensive drugs include chlorothiazide, hydrochlorothiazide, hydroflumethiazide, meticlotiazide, polythiazide, cypamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxy mexrenone (eprerenone), mono Guanetidine sulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tartatrol hydrochloride , Seriprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, chloranolol hydrochloride, bevantol hydrochloride (beba ), Clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine, nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, furanidipine hydrochloride (manidipine), rasidipine, isradipine, valnidipine hydrochloride (methapidipine hydrochloride, ethanol) , Sinaldipine (silnidipine), alanidipine, lercanidipine hydrochloride (masnidipine), azelnidipine, amlodipine, manidipine (furanidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol rollol, cartrolol hydrochloride , Prazosin hydrochloride, urapidil, hydrochloric acid a Nandamine, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinoprilate, fosinoprilate , Trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilate, zofenoprilate, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradrol), phosphosidemine, ketanserin, pinacidil, cicletanide (cicletanide) Amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, mesi Eprosartan acid, candesartan cilexetil (hexetyl), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesylate, cadralazine, rilmenidine dihydrogen phosphate, bosentan, beraprost sodium, limaprost alphadex (α-cyclodextrin), uniprost (treprodextrin) Stynyl sodium), iloprost (cyloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, chlorichromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlorthalidone, quinetazone, indapamide, metolazone, phenoxybenzamine hydrochloride, tyrosine Diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, resell Is one or more agents selected from the group consisting of down and methyldopa above [72] hyperlipidemia preventive or therapeutic pharmaceutical composition.

[74] The pharmaceutical composition for preventing or treating hyperlipidemia according to the above [29], which is used in combination with a therapeutic agent for thrombosis.

[75] The therapeutic agent for thrombosis is one or more drugs selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, antithrombin preparations, antiplatelet agents and thrombolytic agents. A pharmaceutical composition for preventing or treating hyperlipidemia according to [74] above.

[76] The therapeutic agent for thrombosis is heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, leviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human antithrombin III , Aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, ozagrel sodium, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasarplase, nateplase, monteplase, pamiteplase, batroxobin C, and citric acid C [75] above which is one or more drugs selected from the group Hyperlipidemia preventive or therapeutic pharmaceutical composition.

[77] The pharmaceutical composition for preventing or treating obesity according to [30] above, which is used in combination with a therapeutic drug for hyperlipidemia.

[78] Antihyperlipidemic drugs are HMG-CoA reductase inhibitor (statin), fibrate, TNFSF6 expression inhibitor, HDL-cholesterol increase agent, apoA1 expression enhancer, SPP1 (osteopontin) expression inhibitor, peroxisome proliferation Agents that act on factor-activated receptors (PPARs), PPARα agonists, lipase clarifier stimulants, cholesterol antagonists, platelet anticoagulants, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor upregulators, The pharmaceutical composition for preventing or treating obesity according to the above [77], which is one or more drugs selected from the group consisting of bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acid.

[79] Antihyperlipidemic drugs are lovastatin, pravastatin (eptatinatin) sodium, fluvastatin (fluindostatinin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (simvinolin), pitavastatin (italavastatin, nisvastatin) calcium, Lonifibrate (Lonifibrate), Vinifibrate (Vinifibrate), Clinofibrate, Cyprofibrate, Clofibrate, Etofibrate, Fenofibrate, Bezafibrate, Gemfibrozil, Acipimox, Eicosapentaenoic acid (icosapentate, icopenate, icosapentate) , Probucol, policosanol, colesevelam hydrochloride, cholestyramine (cholestyramine resin), cohydrochloride The pharmaceutical composition for preventing or treating obesity according to the above [78], which is one or more drugs selected from the group consisting of restipol, colestimide (cholestilan), ezetimibe and niacin (nicotinic acid).

[80] The pharmaceutical composition for preventing or treating obesity according to the above [30], which is used in combination with a therapeutic agent for diabetes.

[81] The therapeutic agent for diabetes is an insulin secretagogue, biguanide, α-glucosidase inhibitor, insulin preparation, insulin analog, insulin sensitivity enhancer, IL-11, anti-C
D25 (IL-2 receptor) agent, angiotensin (AT1) antagonist, angiotensin converting enzyme (ACE) inhibitor, aldose reductase inhibitor, antioxidant, carnitine acetyltransferase stimulant, antidepressant, glucocorticoid, retilin, radical The pharmaceutical composition for preventing or treating obesity according to the above [80], which is one or more drugs selected from the group consisting of a formation agonist and a transketolase activator.

[82] Antidiabetic drugs include nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybsol, glipizide, gluconeuride, glyquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epallet Miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate / biotin, V-411, recombinant human interleukin-11, dasiliximab (dacilitumab), losartan potassium, captopril, imidapril hydrochloride, α-lipoic acid, lebasecarnin hydrochloride (Acetyl-L-carnitine, acetyl levocarnitine), captopril, retilin, verteporfin, benfotiamine and fluocinolone Is one or more agents selected from the group consisting of Tonido above [81] obesity preventing or therapeutic pharmaceutical composition.

[83] The pharmaceutical composition for preventing or treating obesity according to the above [30], which is used in combination with another therapeutic agent for obesity.

[84] Other anti-obesity drugs include mazindol, lipase inhibitors, 5-HT / norepinephrine reuptake dual inhibitors, 5-HT reuptake inhibitors, herbal ephedrine and caffeine supplements, human chorionic gonadotropin The pharmaceutical composition for prevention or treatment of obesity according to the above [83], which is one or more drugs selected from the group consisting of an adrenergic receptor agonist, methamphetamine, fentamine and amfepramon.

[85] Other obesity medications include mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using the NCP system, metallaminol, d-methamphetamine hydrochloride, phen The pharmaceutical composition for preventing or treating obesity according to the above [84], which is one or more drugs selected from the group consisting of theremin, amfepramon hydrochloride (diethylpropion), benzphetamine hydrochloride, and phendimetrazine tartrate.

[86] The pharmaceutical composition for preventing or treating obesity according to [30] above, which is used in combination with a drug for treating hypertension.

[87] Antihypertensive drugs are thiazide, aldosterone antagonist, adrenergic neuron blocker, calcium channel blocker, dopamine D2 antagonist, β-adrenergic receptor antagonist, α2-adrenergic receptor agonist, guanylic acid Cyclase activator, β1-adrenergic receptor antagonist, α1-adrenergic receptor antagonist, antioxidant, angiotensin-I converting enzyme (ACE) inhibitor, Na ⁺ / H ⁺ exchange inhibitor, α-adrenergic receptor Antagonist, nitric oxide donor, 5-HT2 antagonist, K (ATP) channel activator, potassium-retaining diuretic prostaglandin synthase stimulator, imidazoline I1 receptor agonist, angiotensin AT1 antagonist, dopamine D1 agonist Agent, guanylate cyclase stimulant, endothelin ETA receptor antagonist, endothelin ETB receptor antagonist, NOS3 expression enhancer, prostasai Kulin analog, prostaglandin, angiotensin II antagonist, electrolyte absorption agonist, nicotine antagonist, dopamine D2 agonist, prolactin inhibitor, platelet activating factor (PAF) antagonist, platelet coagulation antagonist, tumor necrosis factor antagonist [86] above, which is one or more drugs selected from the group consisting of: a Rho kinase inhibitor, a PPARα agonist, an AMPA receptor modulator, a GABA (A) receptor antagonist, and a phosphodiesterase V (PDE5A) inhibitor. A pharmaceutical composition for preventing or treating obesity.

[88] Antihypertensive drugs are chlorothiazide, hydrochlorothiazide, hydroflumethiazide, meticlotiazide, polythiazide, cypamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxy mexrenone (eprerenone), mono Guanetidine sulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tartatrol hydrochloride , Seriprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, chloranolol hydrochloride, bevantol hydrochloride ( ), Clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine, nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, furanidipine hydrochloride (manidipine), rasidipine, isradipine, valnidipine hydrochloride (methapidipine hydrochloride, ethanol) , Sinaldipine (silnidipine), alanidipine, lercanidipine hydrochloride (masnidipine), azelnidipine, amlodipine, manidipine (furanidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol rollol, cartrolol hydrochloride , Prazosin hydrochloride, urapidil, hydrochloric acid Nandamine, bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinoprilate, fosinoprilate , Trandolapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilate, zofenoprilate, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradrol), phosphosidemine, ketanserin, pinacidil, cicletanide (cicletanide) Amosulalol hydrochloride, moxonidine hydrochloride hydrate, losartan potassium, valsartan, meso Eprosartan formate, candesartan cilexetil (hexetyl), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesylate, cadralazine, rilmenidine dihydrogen phosphate, bosentan, beraprost sodium, limaprost alphadex (α-cyclodextrin), uniprost (tredextrin) (Prostinyl sodium), iloprost (cyloprost), mecamylamine hydrochloride, metergoline, guanabenz acetate, chlorichromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlorthalidone, kinetazone, indapamide, metolazone, phenoxybenzamine hydrochloride, , Diazoxide, torasemide (torsemide), clopamide, hydralazine hydrochloride, resell The pharmaceutical composition for preventing or treating obesity according to the above [87], which is one or more drugs selected from the group consisting of pin and methyldopa.

[89] The pharmaceutical composition for preventing or treating obesity according to the above [30], wherein the pharmaceutical composition is used in combination with a therapeutic agent for thrombosis.

[90] The therapeutic agent for thrombosis is one or more drugs selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, antithrombin preparations, antiplatelet agents and thrombolytic agents. A pharmaceutical composition for preventing or treating obesity according to [89] above.

[91] The therapeutic agent for thrombosis is heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, leviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human antithrombin III , Aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, ozagrel sodium, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasarplase, nateplase, monteplase, pamiteplase, batroxobin C, and citric acid C The above-mentioned [90], which is one or more drugs selected from the group A pharmaceutical composition for preventing or treating obesity.

[92] The pharmaceutical composition for preventing or treating diabetic complications according to the above [31], which is used in combination with a therapeutic drug for hyperlipidemia.

[93] Hyperlipidemia drugs are HMG-CoA reductase inhibitor (statin), fibrate, TNFSF6 expression inhibitor, HDL-cholesterol increase agent, apoA1 expression enhancer, SPP1 (osteopontin) expression inhibitor, peroxisome proliferation Agents that act on factor-activated receptors (PPARs), PPARα agonists, lipase clarifier stimulants, cholesterol antagonists, platelet anticoagulants, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptor upregulators, The pharmaceutical composition for preventing or treating diabetic complications according to the above [92], which is one or more drugs selected from the group consisting of bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acid.

[94] Drugs for treating hyperlipidemia are lovastatin, pravastatin (eptastatin) sodium, fluvastatin (fluindostatinin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (simvinolin), pitavastatin (itavastatin, nisvastatin) calcium, Lonifibrate (Lonifibrate), Vinifibrate (Vinifibrate), Clinofibrate, Cyprofibrate, Clofibrate, Etofibrate, Fenofibrate, Bezafibrate, Gemfibrozil, Acipimox, Eicosapentaenoic acid (icosapentate, icopenate, icosapentate) , Probucol, policosanol, colesevelam hydrochloride, cholestyramine (cholestyramine resin), cohydrochloride The pharmaceutical composition for preventing or treating diabetic complications according to the above [93], which is one or more drugs selected from the group consisting of restipol, colestimide (cholestilan), ezetimibe and niacin (nicotinic acid).

[95] The pharmaceutical composition for preventing or treating diabetic complications according to the above [31], which is used in combination with a therapeutic agent for diabetes.

[96] Antidiabetic drugs include insulin secretagogues, biguanides, α-glucosidase inhibitors, insulin preparations, insulin analogs, insulin sensitivity enhancers, IL-11, anti-CD25 (IL-2 receptor) agents, angiotensin ( AT1) antagonist, angiotensin converting enzyme (ACE) inhibitor, aldose reductase inhibitor, antioxidant, carnitine acetyltransferase stimulant, antidepressant, glucocorticoid, retilin, radical formation agonist and transketolase activator The pharmaceutical composition for preventing or treating diabetic complications according to the above [95], which is one or more drugs selected from the group.

[97] Antidiabetic drugs include nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybazole, glipizide, gluconeuride, glyquidone, repaglinide, metformin hydrochloride, buformin hydrochloride, voglibose, acarbose, epallet Miglitol, insulin, pioglitazone hydrochloride, rosiglitazone maleate, chromium picolinate / biotin, V-411, recombinant human interleukin-11, dasiliximab (dacilitumab), losartan potassium, captopril, imidapril hydrochloride, α-lipoic acid, lebasecarnin hydrochloride (Acetyl-L-carnitine, acetyl levocarnitine), captopril, retilin, verteporfin, benfotiamine and fluocinolone Is one or more agents selected from the group consisting of Tonido above [96] diabetic complications prophylactic or therapeutic pharmaceutical composition.

[98] The pharmaceutical composition for preventing or treating diabetic complications according to the above [31], which is used in combination with a therapeutic agent for obesity.

[99] A therapeutic agent for obesity is mazindol, a lipase inhibitor, a 5-HT / norepinephrine reuptake dual inhibitor, a 5-HT reuptake inhibitor, a supplement containing herbal ephedrine and caffeine, human chorionic gonadotropin, adrenaline The pharmaceutical composition for preventing or treating diabetic complications according to the above [98], which is one or more drugs selected from the group consisting of a receptor agonist, methamphetamine, fentamine and amfepramon.

[100] Anti-obesity drugs include mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using the NCP system, metallaminol, d-methamphetamine hydrochloride, phentermine, The pharmaceutical composition for preventing or treating diabetic complications according to the above [99], which is one or more drugs selected from the group consisting of amfepramon hydrochloride (diethylpropion), benzphetamine hydrochloride, and phendimetrazine tartrate.

[101] The pharmaceutical composition for preventing or treating diabetic complications according to the above [31], which is used in combination with a therapeutic agent for hypertension.

[102] Antihypertensive drugs are thiazide, aldosterone antagonist, adrenergic neuron blocker, calcium channel blocker, dopamine D2 antagonist, β-adrenergic receptor antagonist, α2-adrenergic receptor agonist, guanylic acid Cyclase activator, β1-adrenergic receptor antagonist, α1-adrenergic receptor antagonist, antioxidant, angiotensin-I converting enzyme (ACE) inhibitor, Na ⁺ / H ⁺ exchange inhibitor, α-adrenergic receptor Antagonist, nitric oxide donor, 5-HT2 antagonist, K (ATP) channel activator, potassium-retaining diuretic prostaglandin synthase stimulator, imidazoline I1 receptor agonist, angiotensin AT1 antagonist, dopamine D1 agonist Agent, guanylate cyclase stimulant, endothelin ETA receptor antagonist, endothelin ETB receptor antagonist, NOS3 expression enhancer, prostasa Iclin analog, prostaglandin, angiotensin II antagonist, electrolyte absorption agonist, nicotine antagonist, dopamine D2 agonist, prolactin inhibitor, platelet activating factor (PAF) antagonist, platelet coagulation antagonist, tumor necrosis factor antagonist [101] The above [101], which is one or more drugs selected from the group consisting of: a Rho kinase inhibitor, a PPARα agonist, an AMPA receptor modulator, a GABA (A) receptor antagonist, and a phosphodiesterase V (PDE5A) inhibitor. A pharmaceutical composition for preventing or treating diabetic complications.

[103] Antihypertensive drugs are chlorothiazide, hydrochlorothiazide, hydroflumethiazide, meticlotiazide, polythiazide, cypamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxy mexrenone (eprerenone), mono Guanetidine sulfate, guanadrel sulfate, verapamil, propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tartatrol hydrochloride , Seriprolol hydrochloride, tilisolol hydrochloride, nebivolol, penbutolol sulfate, nadolol, chloranolol hydrochloride, bevantol hydrochloride ( Vantrol), clonidine, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine, nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, furanidipine hydrochloride
(Manidipine), racidipine, isradipine, varnidipine hydrochloride (mepilodipine), efonidipine hydrochloride, ethanol, sinaldipine (silnidipine), alanidipine, lercanidipine hydrochloride (masnidipine), azelnidipine, amlodipine, manidipine (furanidipine), nitroprusside sodium, atenoproxol hydrochloride, sodium , Bopindolol, bisoprolol fumarate, esmolol hydrochloride, carvedilol, metoprolol succinate, tarinolol, prazosin hydrochloride, urapidil, indramin hydrochloride,
Bunazosin hydrochloride, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinoprilate, fosnoprilate Drapril, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilate, zofenoprilate, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradrol), phosphosidemine, ketanserin, pinacidil, cicletanol hydrochloride (cicletanadol hydrochloride) , Moxonidine hydrochloride hydrate, Losartan potassium, Valsartan, Eprosa mesylate Tan, candesartan cilexetil (hexetyl), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesylate, cadralazine, rilmenidine dihydrogen phosphate, bosentan, beraprost sodium, limaprost alphadex (α-cyclodextrin), uniprost (treprostinil) Sodium), iloprost (cyloprost), mecamylamine hydrochloride, metorgoline, guanabenz acetate, chloricchromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlorthalidone, quinetazone, indapamide, metolazone, phenoxybenzazomine hydrochloride, methytyrosine hydrochloride, Torasemide (torsemide), clopamide, hydralazine hydrochloride, reserpine and methi Is one or more agents selected from the group consisting of dopa the [102] diabetic complications prophylactic or therapeutic pharmaceutical composition.

[104] The pharmaceutical composition for preventing or treating diabetic complications according to the above [31], which is used in combination with a thrombosis therapeutic agent.

[105] The therapeutic agent for thrombosis is one or more drugs selected from the group consisting of heparin preparations, low molecular weight heparins, heparin analogs, anticoagulants, thrombin inhibitors, antithrombin preparations, antiplatelet agents and thrombolytic agents. A pharmaceutical composition for preventing or treating diabetic complications according to [104] above.

[106] The therapeutic agent for thrombosis is heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, leviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human antithrombin III , Aspirin, dipyridamole, ticlopidine hydrochloride, cilostazol, limaprost alfadex, ozagrel sodium, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tisokinase, alteplase, nasarplase, nateplase, monteplase, pamiteplase, batroxobin C, and citric acid C [105] above which is one or more drugs selected from the group Diabetic complications pharmaceutical composition for preventing or treating placement.

[107] A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic drug for hyperlipidemia.

[108] A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for diabetes.

[109] A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for obesity.

[110] A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for hypertension.

[111] A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for thrombosis.

[112] General formula [II]

[Where,
Y ¹⁰⁰ represents —C (R ¹³ ) (R ¹⁴ ) — (R ¹³ and R ¹⁴ are each as described in [1] above);
R ¹⁰⁰ represents a hydroxyl group or a halogen atom;
V, W, and R ³ are as described in [1] above. Or a pharmaceutically acceptable salt thereof.

[113] In the general formula [II], R ¹³ and R ¹⁴ each represents a hydrogen atom, V represents = CH-, and W represents -S-. Its pharmaceutically acceptable salt.

  As shown in the test results and the like described later, it is shown that the compound [I] according to the present invention has an excellent PTP1B inhibitory action and blood glucose lowering action. That is, the compound [I] according to the present invention is expected as a preventive or therapeutic agent for a new type of diabetes that can directly improve insulin action and improve a hyperglycemic state. In addition, the compound [I] according to the present invention is a complication of diabetes (retinopathy, nephropathy, neuropathy, syndrome X or metabolic syndrome, ischemic heart disease (myocardial infarction, angina, etc.) and stroke (cerebral infarction). , Cerebral hemorrhage, subarachnoid hemorrhage, etc.), hyperlipidemia and obesity preventive or therapeutic agent, and further, it is also expected as a prophylactic or therapeutic agent for PTP1B-mediated diseases.

  Furthermore, as shown in the test results described below, the compound [I] according to the present invention has a hypoglycemic ability when administered in combination with each of insulin, glibenclamide, tolbutamide, nateglinide, metformin hydrochloride, voglibose and pioglitazone hydrochloride. Because of its potentiating action, other antidiabetic drugs (especially those other than diabetic complications, including insulin preparations, insulin secretagogues, biguanides, α-glucosidase inhibitors and insulin sensitivity enhancers) In combination with a corresponding therapeutic agent) mutually enhance and / or complement the blood glucose (fasting, postprandial) reducing ability of each of the compound [I] according to the present invention and another therapeutic agent for diabetes. Expected to have. Further, the compound [I] according to the present invention is used in combination with other antidiabetic drugs (especially therapeutic drugs for diabetic complications) to improve hyperglycemia and prevent diabetic complications (particularly microvascular complications). Or it is expected that treatment can be realized simultaneously. Furthermore, the compound [I] according to the present invention can be used in combination with other anti-hyperlipidemic agents, anti-obesity agents, anti-hypertensive agents and / or anti-thrombotic agents, thereby increasing hyperglycemia and high blood lipids. It is expected to improve the obesity state and thus prevent and / or suppress the progression to diabetic complications (particularly macrovascular complications). That is, the compound [I] according to the present invention is used in combination with other antidiabetic drugs, other hyperlipidemia drugs, other obesity drugs, hypertension drugs or thrombosis drugs. It is expected to show an effect of preventing or treating high diabetes and diabetic complications that cannot be exhibited by the therapeutic agent alone.

The definition of each substituent and each site used in the present specification is as follows.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

The “C _1-4 alkyl group” represents a linear or branched alkyl group having 1 to 4 carbon atoms, specifically a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, sec. -A butyl group and a tert- butyl group are mentioned.
Preferably, R ¹ and R ² are methyl groups, and R ¹³ , R ¹⁴ , R ¹⁹ , R ²² and R ²⁵ are methyl groups and ethyl groups.

The “C _1-6 alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec -Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, hexyl group and the like can be mentioned. Preferably, a methyl group, an ethyl group, or a branched alkyl group having 3 to 6 carbon atoms (for example, isopropyl group, isobutyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, etc.) ).
R ⁴ is preferably a methyl group, an ethyl group or an isopentyl group, R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ or R ¹⁰ is a methyl group or an isobutyl group, and R ¹⁵ or R ¹⁶ is a methyl group. Group, ethyl group, isopropyl group, R ¹⁷ is methyl group, isobutyl group, R ²⁰ , R ²¹ are methyl group, isopentyl group, R ¹⁸ , R ²³ , R ²⁴ are methyl group, isobutyl group, a tert-butyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, and a 1-ethylpropyl group;

The “C _1-8 alkyl group” represents a linear or branched alkyl group having 1 to 8 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec -Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, hexyl group, 2-ethylbutyl group, 3,3-dimethylbutyl group, heptyl group, 1- A propylbutyl group, a 3-ethylpentyl group, an octyl group, etc. are mentioned. Preferably, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a branched alkyl group having 4 to 8 carbon atoms (for example, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group) Group, 1-ethylpropyl group, 2-ethylbutyl group, 1-propylbutyl group, etc.).
R ³ is preferably a methyl group, a tert-butyl group, or a 1-ethylpropyl group, and R ¹¹ and R ¹² are each a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group. A butyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a 1-ethylpropyl group, a 2-ethylbutyl group, and a 1-propylbutyl group. R ¹¹ and R ¹² are particularly preferably an isopropyl group.

The “C _1-4 haloalkyl group” represents a haloalkyl group in which a linear or branched alkyl group having 1 to 4 carbon atoms is substituted with the “halogen atom” defined above, specifically, a fluoromethyl group, difluoro Examples thereof include a methyl group, a trifluoromethyl group, a bromomethyl group, a chloromethyl group, a 1,2-dichloromethyl group, a 2,2-dichloromethyl group, and a 2,2,2-trifluoroethyl group. A trifluoromethyl group is preferred.
R ³ is preferably a trifluoromethyl group.

The “C _1-4 alkylene group” represents a linear or branched alkylene group having 1 to 4 carbon atoms, and examples thereof include a methylene group, an ethylene group, a trimethylene group, a propylene group, and a tetramethylene group. Preferably they are a methylene group and ethylene group, More preferably, it is a methylene group.
Preferably, A is a methylene group or ethylene group, and A ¹ is a methylene group.

The “C _1-4 alkoxy group” represents a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, Examples thereof include a tert-butoxy group. Preferably it is a methoxy group.
Preferably, R ²² and R ²⁵ are methoxy groups.

The “C _1-6 alkoxy group” represents a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, Examples thereof include a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, a 1-ethylpropoxy group, and a hexyloxy group. Preferably, a methoxy group, an ethoxy group, or a C3-C6 branched chain alkoxy group (isopropoxy group, isobutoxy group, tert-butoxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-ethyl group) Propoxy group, etc.).
R ³ is preferably a methoxy group, an ethoxy group, an isopropoxy group, an isobutoxy group, a tert-butoxy group, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, or a 1-ethylpropoxy group.

The “aryl group” represents an aromatic hydrocarbon group having 6 to 14 carbon atoms, specifically, phenyl group, naphthyl group, biphenylyl group (for example, 2-biphenylyl group, 3-biphenylyl group, 4-biphenylyl group). Etc.) and anthryl group. Preferably they are a phenyl group, a naphthyl group, and a biphenylyl group, More preferably, it is a phenyl group.
Preferably, Z is a phenyl group or biphenylyl group, B or E is a phenyl group, R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ and R ²¹ are a phenyl group and a naphthyl group. Z is particularly preferably a phenyl group.

  "Heterocyclic group" represents "saturated or unsaturated 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom" Specifically, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydrofuryl, tetrahydrothienyl Group, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, tetrahydropyranyl group, dioxanyl group, piperidinyl group, piperazinyl group, morpholinyl group, etc., preferably

A heterocyclic group selected from the group consisting of

“Aromatic heterocyclic group” means “monocyclic or condensed 5- to 14-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom” Ring group '', specifically, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, Pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, isoindolyl group, benzofuranyl group, benzothienyl group, benzoimidazolyl group, benzothiazolyl group, benzoxazolyl group, indolizinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, cinnolinyl group, quinoxalinyl Group, phthalazinyl group, acridinyl group, phenazi Group, naphthyridinyl group, and the like. Preferably, it is “a monocyclic or condensed 5- to 10-membered aromatic heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom”, and furyl Group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, indolyl group, Examples thereof include an isoindolyl group, a benzofuranyl group, a benzothienyl group, a benzoimidazolyl group, a benzothiazolyl group, a benzoxazolyl group, an indolizinyl group, a quinolyl group, and an isoquinolyl group.

Preferably, B is a thienyl group, thiazolyl group, pyrazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, indolyl group, benzoimidazolyl group, benzothiazolyl group, benzoxazolyl group, E Are a furyl group, an isoxazolyl group and a pyridyl group, Z is a thienyl group and a pyridyl group, and R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ²¹ are an oxazolyl group, a thiazolyl group, a pyridyl group, a benzothienyl group, a benzimidazolyl group, and a quinolyl group.

The “C _3-7 cycloalkyl group” is a cycloalkyl group having 3 to 7 carbon atoms, and specifically a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Preferred is a cycloalkyl group having 5 to 7 carbon atoms, and particularly preferred is a cyclohexyl group.
Preferably, Z is a cyclohexyl group.

The “C _2-4 alkenyl group” represents a linear or branched alkenyl group having 2 to 4 carbon atoms, specifically, a vinyl group, 1-propenyl group, allyl group, 1-methyl-2-propenyl group. 1-butenyl group, 2-butenyl group, 3-butenyl group and the like.
Preferably, R ¹¹ and R ¹² are allyl groups.

The “C _1-4 alkylsulfonyl group” is an alkylsulfonyl group having the above-defined “C _1-4 alkyl group” as an “alkyl” moiety, and specifically includes a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group. Group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group and tert-butylsulfonyl group.
R ¹¹ , R ¹² , R ²³ , and R ²⁴ are preferably methylsulfonyl groups (that is, mesyl groups).

The “C _1-4 alkylcarbonyl group” is an alkylcarbonyl group having the above-defined “C _1-4 alkyl group” as an “alkyl” moiety, and specifically includes an acetyl group, a propionyl group, a butyryl group, an isobutyryl group. Group, valeryl group, isovaleryl group, pivaloyl group and the like.
Preferably, R ¹¹ and R ¹² are acetyl groups, and R ²³ and R ²⁴ are acetyl groups and isobutyryl groups.

The “C _1-4 alkoxycarbonyl group” is an alkoxycarbonyl group having the “C _1-4 alkoxy group” defined above as an “alkoxy” moiety, and specifically includes a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group. Group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, tert-butoxycarbonyl group and the like.

  The “aryloxy group” is an aryloxy group having the above-defined “aryl group” as the “aryl” moiety, and specific examples include a phenoxy group and a naphthyloxy group.

The “aralkyl group” is a “C _1-4 alkyl group” substituted with an “aryl group”, and the “aryl group” and “C _1-4 alkyl group” are as defined above. Specific examples of the “aralkyl group” include a benzyl group.

The “C _1-4 alkylamino group” is an alkylamino group having the above-defined “C _1-4 alkyl group” as an “alkyl” moiety, and specifically includes a methylamino group, an ethylamino group, propyl Amino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group and the like can be mentioned.

The “C _1-6 alkylamino group” is an alkylamino group having the above-defined “C _1-6 alkyl group” as an “alkyl” moiety, and specifically includes a methylamino group, an ethylamino group, a propyl Amino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, pentylamino group, isopentylamino group, neopentylamino group, tert-pentylamino group, hexylamino group Etc.
Preferably, in R ²² and R ²⁵ , methylamino group, ethylamino group, isopropylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, isopentylamino group, neopentylamino group, tert-pentyl group It is an amino group.

The “di (C _1-4 alkyl) amino group” is a di (alkyl) amino group having the above-defined “C _1-4 alkyl group” as an “alkyl” moiety, specifically a dimethylamino group. , Diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di (sec-butyl) amino group, di (tert-butyl) amino group, N-ethyl-N-methylamino group, N -Methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The “di (C _1-6 alkyl) amino group” is a di (alkyl) amino group having the above-defined “C _1-4 alkyl group” as an “alkyl” moiety, specifically, a dimethylamino group , Diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di (sec-butyl) amino group, di (tert-butyl) amino group, dipentylamino group, diisopentylamino group, di (Tert-pentyl) amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like can be mentioned.
Preferably, R ²² and R ²⁵ are dimethylamino group, diethylamino group, dipropylamino group, dibutylamino group, dipentylamino group, diisopentylamino group, dihexylamino group, N-ethyl-N-methylamino group, N -Methyl-N-propylamino group, N-ethyl-N-propylamino group.

The “C _1-6 alkylthio group” is an alkylthio group having the above-defined “C _1-6 alkyl group” as an “alkyl” moiety, and specifically includes a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group. Group, butylthio group, isobutylthio group, sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, 1-ethylpropylthio group, hexylthio group, etc. .
R ²² and R ²⁵ are preferably a methylthio group.

“Di (C _1-6 alkyl) aminocarbonyl group” means a di (alkyl) having the above-defined “di (C _1-6 alkyl) amino group” as the “di (C _1-6 alkyl) amino” moiety. Aminocarbonyl group, specifically, dimethylaminocarbonyl group, diethylaminocarbonyl group, dipropylaminocarbonyl group, diisopropylaminocarbonyl group, dibutylaminocarbonyl group, diisobutylaminocarbonyl group, di (sec-butyl) aminocarbonyl group Di (tert-butyl) aminocarbonyl group, dipentylaminocarbonyl group, diisopentylaminocarbonyl group, di (tert-pentyl) aminocarbonyl group, dihexylaminocarbonyl group, N-ethyl-N-methylaminocarbonyl group, N -Methyl-N-propylaminocarboni Group, such as N- ethyl -N- propylamino carbonyl group.

Of -COO (R ¹⁹⁾ moiety in R, if R ¹⁹ is a hydrogen atom, the carboxy group may form a salt. Examples of the salt include alkali metal salts (for example, potassium salts and sodium salts), alkaline earth metal salts (for example, calcium salts and magnesium salts) and the like. Preferred are sodium salt and calcium salt.

The “C _1-6 alkyl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is an aryl group that may be substituted, an aromatic heterocyclic group that may be substituted, carboxy, C _1-4 alkoxycarbonyl ^{group, -CO-N (R 15)} (R 16), - N (R 15) (R 16), - O-R 17, -CO-R 17, -SO 2 It may be substituted with —R ¹⁷ or a C _3-7 cycloalkyl group. Such a “C _1-6 alkyl group” may be a C _1-6 alkyl group substituted with a plurality of substituents such as a benzhydryl group. Preferably, the number of substituents is 1. When the “C _1-6 alkyl group” is substituted, the “C _1-6 alkyl group” portion is preferably a methyl group.

The “aryl group” part of the “optionally substituted aryl group” which is a substituent on the “C _1-6 alkyl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ Is an “aryl group” as defined above, and is preferably a phenyl group or a naphthyl group.

The “ _optionally substituted aryl group” as a substituent on the “C _1-6 alkyl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is selected from the following: It may be substituted with 1 to 3 selected substituents. Examples of the substituent include a halogen atom, C _1-8 alkyl groups, di (C _1-6 alkyl) C _1-8 alkyl group substituted with aminocarbonyl group, C _1-4 haloalkyl group, C _1-4 alkoxy Group, C _2-4 alkenyl group, carboxy group, hydroxyl group, cyano group, nitro group, amino group, C _1-4 alkylamino group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group Group, morpholino group, C _1-4 alkoxycarbonyl group, C _1-6 alkylthio group, aromatic heterocyclic group which may be substituted with halogen atom, aralkyl group and the like. Preferred substituents are halogen atoms (eg, fluorine atom, chlorine atom, etc.), C _1-8 alkyl groups (eg, methyl group, isopropyl group, tert-butyl group, 1-propylbutyl group, etc.), C _1-4 Haloalkyl group (eg, trifluoromethyl group, etc.), C _2-4 alkenyl group (eg, allyl group, etc.), C _1-6 alkylthio group (eg, methylthio group, etc.), di (C _1-6 alkyl) aminocarbonyl A C _1-8 alkyl group (eg, methyl group) substituted with a group (eg, diethylaminocarbonyl group), an aromatic heterocyclic group (eg, chlorine atom) optionally substituted with a halogen atom (eg, chlorine atom) Thienyl group, imidazolyl group and the like) and aralkyl group (for example, benzyl group and the like).

“Aromaticity” of “optionally substituted aromatic heterocyclic group” which is a substituent on “C _1-6 alkyl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ The “aromatic heterocyclic group” moiety is the “aromatic heterocyclic group” defined above, and is preferably an oxazolyl group, a thiazolyl group, a pyridyl group, a benzothienyl group, a benzimidazolyl group, or a quinolyl group.

The “ _optionally substituted aromatic heterocyclic group” which is a substituent on the “C _1-6 alkyl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is 1 to 3 substituents selected from among them may be substituted. Examples of the substituent include a halogen atom, C _1-8 alkyl groups, di (C _1-6 alkyl) C _1-8 alkyl group substituted with aminocarbonyl group, C _1-4 haloalkyl group, C _1-4 alkoxy Group, C _2-4 alkenyl group, carboxy group, hydroxyl group, cyano group, nitro group, amino group, C _1-4 alkylamino group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group Groups, morpholino groups, C _1-4 alkoxycarbonyl groups, C _1-6 alkylthio groups, aryl groups which may be substituted with halogen atoms, aromatic heterocyclic groups which may be substituted with halogen atoms, aralkyl groups and the like. It is done. Preferred substituents are halogen atoms (eg, fluorine atom, chlorine atom, etc.), C _1-8 alkyl groups (eg, methyl group, isopropyl group, tert-butyl group, 1-propylbutyl group, etc.), C _1-4 Haloalkyl group (for example, trifluoromethyl group), C _2-4 alkenyl group (for example, allyl group), C _1-6 alkylthio group (for example, methylthio group), di (C _1-6 alkyl) aminocarbonyl C _1-8 alkyl group (eg, methyl group) substituted with a group (eg, diethylaminocarbonyl group), aryl group (eg, phenyl group) optionally substituted with a halogen atom (eg, chlorine atom) ), An aromatic heterocyclic group (eg thienyl group, imidazolyl group etc.) which may be substituted with a halogen atom (eg chlorine atom etc.), aralkyl group (eg benzyl group etc.) A.

“C _1-4 alkoxycarbonyl group” which is a substituent on “C _1-6 alkyl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is as defined above. “C _1-4 alkoxycarbonyl group”, preferably an ethoxycarbonyl group, a propoxycarbonyl group, or an isobutoxycarbonyl group.

The “C _3-7 cycloalkyl group” which is a substituent on the “C _1-6 alkyl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is as defined above. “C _3-7 cycloalkyl group”, preferably a cyclohexyl group.

The “optionally substituted aryl group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is substituted with 1 to 3 substituents selected from the following: Also good. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group, aromatic heterocyclic group optionally substituted by halogen atom, aralkyl group Etc. Preferred substituents are halogen atoms (eg, fluorine atom, chlorine atom, etc.), C _1-8 alkyl groups (eg, methyl group, isopropyl group, tert-butyl group, 1-propylbutyl group, etc.), C _1-4 A haloalkyl group (eg, trifluoromethyl group, etc.), an aromatic heterocyclic group (eg, thienyl group, imidazolyl group, etc.) optionally substituted with a halogen atom (eg, chlorine atom), an aralkyl group (eg, benzyl group) Etc.).

The “optionally substituted aromatic heterocyclic group” in R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ is 1 to 3 substituents selected from the following: May be substituted. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group, aryl group which may be substituted with halogen atom, substituted with halogen atom An aromatic heterocyclic group, an aralkyl group and the like may be mentioned. Preferred substituents are halogen atoms (eg, fluorine atom, chlorine atom, etc.), C _1-8 alkyl groups (eg, methyl group, isopropyl group, tert-butyl group, 1-propylbutyl group, etc.), C _1-4 Substituted with a haloalkyl group (eg, trifluoromethyl group), an aryl group (eg, phenyl group) optionally substituted with a halogen atom (eg, chlorine atom), or a halogen atom (eg, chlorine atom) And an aromatic heterocyclic group (for example, thienyl group, imidazolyl group and the like) and an aralkyl group (for example, benzyl group and the like).

The “optionally substituted aryl group” for R ¹⁵ , R ¹⁶ and R ¹⁷ may be substituted with 1 to 3 substituents selected from the following. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents include a halogen atom (eg, chlorine atom), a C _1-8 alkyl group (eg, methyl group, isopropyl group, etc.), a C _1-4 alkoxy group (eg, methoxy group, etc.), a carboxy group, a di group. (C _1-4 alkyl) amino group (for example, dimethylamino group and the like).

The “optionally substituted aromatic heterocyclic group” in R ¹⁵ , R ¹⁶ and R ¹⁷ may be substituted with 1 to 3 substituents selected from the following. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents include a halogen atom (eg, chlorine atom), a C _1-8 alkyl group (eg, methyl group, isopropyl group, etc.), a C _1-4 alkoxy group (eg, methoxy group, etc.), a carboxy group, a di group. (C _1-4 alkyl) amino group (for example, dimethylamino group and the like).

R ^15, R ^16, "C _1-6 alkyl group" in R ¹⁷ is optionally substituted aryl group, an optionally substituted aromatic heterocyclic group, optionally C _1-4 substituted with an aryl group It may be substituted with an alkoxy group or an optionally substituted aryloxy group. When the “C _1-6 alkyl group” is substituted, the “C _1-6 alkyl group” is preferably a methyl group.

The “aryl group” portion of the “optionally substituted aryl group” which is a substituent on the “C _1-6 alkyl group” in R ¹⁵ , R ¹⁶ and R ¹⁷ is the “aryl group” defined above. Preferably, they are a phenyl group and a naphthyl group.

The “optionally substituted aryl group” on the “C _1-6 alkyl group” in R ¹⁵ , R ¹⁶ and R ¹⁷ is substituted with 1 to 3 substituents selected from the following: May be. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents include a halogen atom (eg, chlorine atom), a C _1-8 alkyl group (eg, methyl group, isopropyl group, etc.), a C _1-4 alkoxy group (eg, methoxy group, etc.), a carboxy group, a di group. (C _1-4 alkyl) amino group (for example, dimethylamino group, etc.), 1-pyrrolidinyl group, 1-piperidyl group, morpholino group.

The “aromatic heterocyclic group” part of the “optionally substituted aromatic heterocyclic group” which is a substituent on the “C _1-6 alkyl group” in R ¹⁵ , R ¹⁶ and R ¹⁷ is as defined above. “Aromatic heterocyclic group”, preferably oxazolyl group, thiazolyl group, pyridyl group, benzothienyl group, benzoimidazolyl group, quinolyl group.

The “optionally substituted aromatic heterocyclic group” which is a substituent on the “C _1-6 alkyl group” in R ¹⁵ , R ¹⁶ and R ¹⁷ is 1 to 3 substituents selected from the following: It may be substituted with a group. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents include a halogen atom (eg, chlorine atom), a C _1-8 alkyl group (eg, methyl group, isopropyl group, etc.), a C _1-4 alkoxy group (eg, methoxy group, etc.), a carboxy group, a di group. (C _1-4 alkyl) amino group (for example, dimethylamino group, etc.), 1-pyrrolidinyl group, 1-piperidyl group, morpholino group.

And R ^15, R ^16, "C _1-4 alkoxy group" of the "C _1-6 alkyl group" on a substituent "optionally C _1-4 alkoxy group optionally substituted with an aryl group" for R ¹⁷ moiety Is a “C _1-4 alkoxy group” as defined above, preferably a methoxy group.

The “aryl group” part of the “C _1-4 alkoxy group optionally substituted with an aryl group” which is a substituent on the “C _1-6 alkyl group” in R ¹⁵ , R ¹⁶ and R ¹⁷ is the above definition. An “aryl group”, preferably a phenyl group.

The “aryloxy group” part of the “optionally substituted aryloxy group” which is a substituent on the “C _1-6 alkyl group” in R ¹⁵ , R ¹⁶ and R ¹⁷ is the “aryloxy group” defined above. And preferably a phenoxy group.

The “optionally substituted aryloxy group” which is a substituent on the “C _1-6 alkyl group” in R ¹⁵ , R ¹⁶ , and R ¹⁷ is 1 to 3 substituents selected from the following: May be substituted. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents include a halogen atom (eg, chlorine atom), a C _1-8 alkyl group (eg, methyl group, isopropyl group, etc.), a C _1-4 alkoxy group (eg, methoxy group, etc.), a carboxy group, a di group. (C _1-4 alkyl) amino group (for example, dimethylamino group, etc.), 1-pyrrolidinyl group, 1-piperidyl group, morpholino group.

R ¹⁵ and R ¹⁶ are formed together with the nitrogen atom to which they are bonded. “Furthermore, they may contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The “7-membered heterocycle” is preferably “saturated or unsaturated 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom”. ,In particular,

A heterocycle selected from the group consisting of

The “C _1-6 alkyl group” for R ²¹ may be substituted with an optionally substituted aryl group or an optionally substituted aromatic heterocyclic group.

The “aryl group” part of the “optionally substituted aryl group” which is a substituent on the “C _1-6 alkyl group” in R ²¹ is the “aryl group” defined above, preferably a phenyl group. is there.

The “optionally substituted aryl group” which is the substituent on the “C _1-6 alkyl group” in R ²¹ may be substituted with 1 to 3 substituents selected from the following. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents are a halogen atom (eg, chlorine atom, fluorine atom), a C _1-8 alkyl group (eg, methyl group), and a C _1-4 haloalkyl group (eg, trifluoromethyl group).

The “aromatic heterocyclic group” moiety of the “optionally substituted aromatic heterocyclic group” which is a substituent on the “C _1-6 alkyl group” in R ²¹ is the “aromatic heterocyclic group” defined above. And preferably an oxazolyl group, a thiazolyl group, a pyridyl group, a benzothienyl group, a benzoimidazolyl group, or a quinolyl group.

The “optionally substituted aromatic heterocyclic group” which is a substituent on the “C _1-6 alkyl group” in R ²¹ may be substituted with 1 to 3 substituents selected from the following: Good. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents are a halogen atom (eg, chlorine atom, fluorine atom), a C _1-8 alkyl group (eg, methyl group), and a C _1-4 haloalkyl group (eg, trifluoromethyl group).

The “optionally substituted aryl group” for R ²¹ may be substituted with 1 to 3 substituents selected from the following. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents are a halogen atom (eg, chlorine atom, fluorine atom), a C _1-8 alkyl group (eg, methyl group), and a C _1-4 haloalkyl group (eg, trifluoromethyl group).

The “optionally substituted aromatic heterocyclic group” for R ²¹ may be substituted with 1 to 3 substituents selected from the following. Such substituents include halogen atoms, C _1-8 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkylamino groups. Group, di (C _1-4 alkyl) amino group, 1-pyrrolidinyl group, 1-piperidyl group, morpholino group, C _1-4 alkoxycarbonyl group and the like. Preferred substituents are a halogen atom (eg, chlorine atom, fluorine atom), a C _1-8 alkyl group (eg, methyl group), and a C _1-4 haloalkyl group (eg, trifluoromethyl group).

The “C _1-4 alkylcarbonyl group” in R ²³ and R ²⁴ may be substituted with an amino group, a C _1-4 alkylamino group or a di (C _1-4 alkyl) amino group.

R ^23, is a substituent on the "C _1-6 alkylcarbonyl group" in R ²⁴ "C _1-4 alkylamino group" is a defined above, "C _1-4 alkylamino group", preferably It is a methylamino group.

R ^23, is a substituent on the "C _1-6 alkylcarbonyl group" in R ²⁴ and "di (C _1-4 alkyl) amino group", "di (C _1-4 alkyl) amino group as defined above And preferably a dimethylamino group.

The “C _1-8 alkyl group” in R ¹¹ and R ¹² is a C _3-7 cycloalkyl group, an _optionally substituted aryl group, an optionally substituted heterocyclic group, a hydroxyl group, a C _1-4 alkylamino group. And a substituent selected from the group consisting of a di (C _1-4 alkyl) amino group.

The “aryl group” part of the “optionally substituted aryl group” which is a substituent on the “C _1-8 alkyl group” in R ¹¹ and R ¹² is the “aryl group” defined above, preferably It is a phenyl group.

The “optionally substituted aryl group” which is a substituent on the “C _1-8 alkyl group” in R ¹¹ and R ¹² may be substituted with 1 to 3 substituents selected from the following: Good. Such substituents include halogen atoms, C _1-4 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkoxycarbonyls. Groups and the like. A preferred substituent is a halogen atom or a C _1-4 haloalkyl group.

The “heterocyclic group” moiety of the “optionally substituted heterocyclic group” which is a substituent on the “C _1-8 alkyl group” in R ¹¹ and R ¹² is “from a nitrogen atom, an oxygen atom and a sulfur atom” A saturated or unsaturated 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of: a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, and an isoxazolyl. Group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, Pyranyl group, dioxanyl group, piperidinyl group, piperazinyl group, morpholini Group and the like, preferably tetrahydropyranyl group.

The “optionally substituted heterocyclic group” which is a substituent on the “C _1-8 alkyl group” in R ¹¹ and R ¹² is substituted with 1 to 3 substituents selected from the following: Also good. Such substituents include halogen atoms, C _1-4 alkyl groups, C _1-4 haloalkyl groups, C _1-4 alkoxy groups, carboxy groups, hydroxyl groups, cyano groups, nitro groups, amino groups, C _1-4 alkoxycarbonyls. Groups and the like.

R ^11, is a substituent on the "C _1-8 alkyl group" in R ¹² "C _1-4 alkylamino group" is a defined above, "C _1-4 alkylamino group", preferably methyl It is an amino group.

It is a substituent on the "C _1-8 alkyl group" in R ^11, R ¹² 'di (C _1-4 alkyl) amino group "and, in the definition" di- (C _1-4 alkyl) amino group " And preferably a dimethylamino group.

The “C _1-4 alkylcarbonyl group” in R ¹¹ and R ¹² may be substituted with a hydroxyl group or a C _1-4 alkoxy group.

R ^11, is a substituent on the "C _1-4 alkylcarbonyl group" in R ¹² "C _1-4 alkoxy group" is a "C _1-4 alkoxy group" defined above.

The “C _3-7 cycloalkane” formed by R ¹³ and R ¹⁴ together with the carbon atom to which they are bonded is a cycloalkane having 3 to 7 carbon atoms, specifically cyclopropane, cyclobutane. , Cyclopentane, cyclohexane and cycloheptane. Preferred is a cycloalkane having 5 to 7 carbon atoms, and particularly preferred is cyclopentane or cyclohexane.

R ¹³ and R ¹⁴ are formed together with the carbon atom to which they are bonded. “Furthermore, they may contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The “7-membered heterocycle” is preferably “saturated 5- to 7-membered heterocycle which may contain 1 to 3 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom”. Specific examples thereof include tetrahydropyran and thiane, and tetrahydropyran is particularly preferable.

The C _1-4 alkylene group in A may be substituted with a C _3-7 cycloalkyl group. Examples of the C _3-7 cycloalkyl group include the “C _3-7 cycloalkyl group” defined above.

As the “C _1-4 alkylene group _optionally substituted with a C _3-7 cycloalkyl group” in A, preferably,

And more preferably —CH ₂ —.

The “C _3-7 cycloalkyl group” in Z is preferably a cyclopentyl group or a cyclohexyl group, and more preferably a cyclohexyl group.

The “C _3-7 cycloalkyl group” in Z is an aryl group (the aryl group may be substituted with 1 to 5 (preferably 1 to 3) halogen atoms or a C _1-6 alkyl group). Or an aromatic heterocyclic group (the aromatic heterocyclic group may be substituted with 1 to 5 (preferably 1 to 3) halogen atoms or a C _1-6 alkyl group). Good. The substituent of the “C _3-7 cycloalkyl group” is preferably a phenyl group which may be substituted with 1 to 3 halogen atoms or a C _1-6 alkyl group.

  The “aryl group” in Z is preferably a phenyl group or a biphenylyl group (for example, a 2-biphenylyl group, a 3-biphenylyl group, or a 4-biphenylyl group), and more preferably a phenyl group.

The “aryl group” in Z may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from the following.
(a) a heterocyclic group which may be substituted with a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group,
(b) a C _3-7 cycloalkyl group _optionally substituted with a hydroxyl group, an oxo group, a halogen atom or a C _1-6 alkyl group,
(c) a carboxy group,
(d) a halogen atom,
(e) a C _1-8 alkyl group,
(f) a C _1-4 haloalkyl group,
(g) a C _1-4 alkylamino group,
(h) a di (C _1-4 alkyl) amino group,
(i) a C _1-6 alkylthio group,
(j) a C _1-4 alkoxy group,
(k) a C _1-4 alkylcarbonyl group and
(l) Nitro group.
As such a substituent, a C _1-8 alkyl group is preferable.

The “heterocyclic group” in the “heterocyclic group _optionally substituted with a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group” which is a substituent on the “aryl group” in Z is preferably “nitrogen” A saturated or unsaturated 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of an atom, oxygen atom and sulfur atom, specifically, a furyl group, a thienyl group , Pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, pyrazolidinyl group, imidazolidinyl group Oxazolidinyl group, thiazolidinyl group, tetrahydropyranyl group, dioxanyl group, Lysinyl group, a piperazinyl group and a morpholinyl group. Preferred are piperidinyl group, morpholinyl group, piperazinyl group, pyrrolidinyl group, pyrrolyl group and tetrahydropyranyl group.
The substituent on the “heterocyclic group” is preferably a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group.

“C _3-7 cycloalkyl” in “C _3-7 cycloalkyl group _optionally substituted with hydroxyl group, oxo group, halogen atom or C _1-6 alkyl group” which is a substituent on “aryl group” in Z Is preferably a cyclopentyl group or a cyclohexyl group, and more preferably a cyclohexyl group. The “C _3-7 cycloalkyl group” is substituted with 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of a hydroxyl group, an oxo group, a halogen atom and a C _1-6 alkyl group. May be. The substituent on the “C _3-7 cycloalkyl group” is preferably a halogen atom or a C _1-4 alkyl group.

  Examples of the “halogen atom” as a substituent on the “aryl group” in Z include the above-defined “halogen atom”, preferably a fluorine atom, a chlorine atom or a bromine atom, particularly preferably a chlorine atom. It is.

Examples of the “C _1-8 alkyl group” which is a substituent on the “aryl group” in Z include the “C _1-8 alkyl group” defined above. Preferably, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, 1-propylbutyl group, more preferably isopentyl group. , Neopentyl group, tert-pentyl group, 1-ethylpropyl group and 1-propylbutyl group, particularly preferably neopentyl group, 1-ethylpropyl group and 1-propylbutyl group.

Examples of the “C _1-4 haloalkyl group” which is a substituent on the “aryl group” in Z include the “C _1-4 haloalkyl group” defined above, and is preferably a trifluoromethyl group.

Examples of the “C _1-4 alkylamino group” which is a substituent on the “aryl group” in Z include the “C _1-4 alkylamino group” defined above, preferably a methylamino group, an ethylamino group Or it is an isopropylamino group.

Examples of the “di (C _1-4 alkyl) amino group” which is a substituent on the “aryl group” in Z include the “di (C _1-4 alkyl) amino group” defined above, preferably dimethyl An amino group, a diethylamino group or a dipropylamino group.

Examples of the “C _1-6 alkylthio group” which is a substituent on the “aryl group” in Z include the above-defined “C _1-6 alkylthio group”, preferably an isopentylthio group.

Examples of the “C _1-4 alkoxy group” which is a substituent on the “aryl group” in Z include the “C _1-4 alkoxy group” defined above.

Examples of the “C _1-4 alkylcarbonyl group” which is a substituent on the “aryl group” in Z include the “C _1-4 alkylcarbonyl group” defined above, and preferably an acetyl group.

  The “aromatic heterocyclic group” in Z is preferably a monocyclic or condensed ring of 5 to 10 containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. A membered aromatic heterocyclic group ", a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an indolyl group Group, isoindolyl group, benzofuranyl group, benzothienyl group, benzoimidazolyl group, benzothiazolyl group, benzoxazolyl group and the like. Particularly preferred is a thiazolyl group or a pyridyl group.

The “aromatic heterocyclic group” in Z may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from the following.
(a) a heterocyclic group which may be substituted with a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group,
(b) a C _3-7 cycloalkyl group _optionally substituted with a hydroxyl group, an oxo group, a halogen atom or a C _1-6 alkyl group,
(c) a carboxy group,
(d) a halogen atom,
(e) a C _1-8 alkyl group,
(f) a C _1-4 haloalkyl group,
(g) a C _1-4 alkylamino group,
(h) a di (C _1-4 alkyl) amino group,
(i) a C _1-6 alkylthio group,
(j) a C _1-4 alkoxy group,
(k) a C _1-4 alkylcarbonyl group and
(l) An aryl group which may be substituted with a halogen atom or a C _1-4 haloalkyl group.
Such a substituent is preferably (a) a heterocyclic group, (b) a C _1-8 alkyl group, or (c) an aryl group which may be substituted with a halogen atom or a C _1-4 haloalkyl group.

The “heterocyclic group” in the “heterocyclic group optionally substituted with a C _1-4 alkyl group or C _1-4 alkylcarbonyl group” which is a substituent on the “aromatic heterocyclic group” in Z is preferably , “Saturated or unsaturated 5- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom”, specifically, a furyl group , Thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, tetrahydrofuryl group, tetrahydrothienyl group, pyrrolidinyl group, pyrazolidinyl group , Imidazolidinyl group, oxazolidinyl group, thiazolidinyl group, tetrahydropyranyl group, dioxanyl , Piperidinyl group, piperazinyl group and a morpholinyl group. Preferred are piperidinyl group, morpholinyl group, piperazinyl group, pyrrolidinyl group, pyrrolyl group and tetrahydropyranyl group.
The substituent on the “heterocyclic group” is preferably a C _1-4 alkyl group or a C _1-4 alkylcarbonyl group.

“C _3-7 ” in “C _3-7 cycloalkyl group _optionally substituted with hydroxyl group, oxo group, halogen atom or C _1-6 alkyl group” which is a substituent on “aromatic heterocyclic group” in Z “Cycloalkyl” is preferably a cyclopentyl group or a cyclohexyl group, and more preferably a cyclohexyl group. The “C _3-7 cycloalkyl group” is substituted with 1 to 5 (preferably 1 to 3) substituents selected from the group consisting of a hydroxyl group, an oxo group, a halogen atom and a C _1-6 alkyl group. May be. The substituent on the “C _3-7 cycloalkyl group” is preferably a halogen atom or a C _1-4 alkyl group.

  Examples of the “halogen atom” as a substituent on the “aromatic heterocyclic group” in Z include the “halogen atom” defined above, preferably a fluorine atom, a chlorine atom or a bromine atom, particularly preferably. , A chlorine atom.

Examples of the “C _1-8 alkyl group” as a substituent on the “aromatic heterocyclic group” in Z include the “C _1-8 alkyl group” defined above. Preferably, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, 1-propylbutyl group, more preferably isopentyl group. , Neopentyl group, tert-pentyl group, 1-ethylpropyl group and 1-propylbutyl group, particularly preferably neopentyl group, 1-ethylpropyl group and 1-propylbutyl group.
Examples of the “C _1-4 haloalkyl group” which is a substituent on the “aromatic heterocyclic group” in Z include the “C _1-4 haloalkyl group” defined above, preferably a trifluoromethyl group. .

Examples of the “C _1-4 alkylamino group” which is a substituent on the “aromatic heterocyclic group” in Z include the “C _1-4 alkylamino group” defined above, preferably a methylamino group, An ethylamino group or an isopropylamino group.

Examples of the “di (C _1-4 alkyl) amino group” that is a substituent on the “aromatic heterocyclic group” in Z include the “di (C _1-4 alkyl) amino group” defined above, and preferably Is a dimethylamino group, a diethylamino group or a dipropylamino group.

Examples of the “C _1-6 alkylthio group” which is a substituent on the “aromatic heterocyclic group” in Z include the above-defined “C _1-6 alkylthio group”, preferably an isopentylthio group. .

Examples of the “C _1-4 alkoxy group” which is a substituent on the “aromatic heterocyclic group” in Z include the “C _1-4 alkoxy group” defined above.

Examples of the “C _1-4 alkylcarbonyl group” as a substituent on the “aromatic heterocyclic group” in Z include the “C _1-4 alkylcarbonyl group” defined above, and preferably an acetyl group. .

The “aryl group optionally substituted with a halogen atom or a C _1-4 haloalkyl group” which is a substituent on the “aromatic heterocyclic group” in Z is preferably “a halogen atom or a C _1-4 haloalkyl group”. An optionally substituted phenyl group.

The “piperazinyl group” in Z may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from the following.
(a) a phenyl group,
(b) a phenyl C _1-4 alkyl group,
(c) a benzoyl group optionally substituted with a halogen atom and
(d) A phenyl C _1-4 alkoxycarbonyl group.

The “phenyl C _1-4 alkyl group” which is a substituent on the “piperazinyl group” in Z is a phenylalkyl group having the “C _1-4 alkyl group” defined above as the “alkyl moiety”, specifically Include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group and the like. Preferably, it is a benzyl group.

  The “benzoyl group which may be substituted with a halogen atom” which is a substituent on the “piperazinyl group” in Z is preferably a benzoyl group which may be substituted with 1 to 5 “halogen atoms” as defined above. Specific examples include a chlorobenzoyl group and a bromobenzoyl group.

The phenyl C _1-4 alkoxycarbonyl group which is a substituent on the “piperazinyl group” in Z is a phenylalkoxycarbonyl group having the “C _1-4 alkoxy group” defined above as an “alkoxy moiety”, specifically Includes benzyloxycarbonyl group and the like. Preferably, it is a benzyloxycarbonyl group.

In general formula [I], preferred embodiments are as follows.
V is preferably ═N— or ═CH—.
W is preferably -S-.
m is preferably 1 or 2.
R ¹ and R ² are preferably hydrogen atoms.

X is preferably the following (1) to (4).
(1)
_{^{-N (R 4) -, -}} SO 2 -N (R 5) -, - CO-N (R 7) - or -O-
(Wherein R ⁴ represents a hydrogen atom or a C _1-6 alkyl group, R ⁵ represents a hydrogen atom or a C _1-6 alkyl group, and R ⁷ represents a hydrogen atom or a C _1-6 alkyl group),
(2)
-N (R ⁴ )-
(Where R ⁴ is
(a) an aryl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a C _1-8 alkyl group and a C _1-4 haloalkyl group;
(b) an aromatic heterocyclic group optionally substituted by 1 to 3 C _1-8 alkyl groups;
(c) a carboxy group,
(d) a C _1-4 alkoxycarbonyl group,
(e) -CO-N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an aryl group (the aryl group is a C _1-8 alkyl group, a C _1-4 alkoxy group, a carboxy group and a di (C _1-4 alkyl ) Which may be substituted with 1 to 3 substituents selected from the group consisting of amino groups), aromatic heterocyclic groups, C _1-6 alkyl groups (the C _1-6 alkyl groups are aryl groups) Which may be substituted), or together with the nitrogen atom to which they are attached, may further contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A good 5- to 7-membered heterocycle may be formed),
(f) -N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ each independently represents a hydrogen atom or an aryl group),
(g) -O-R ¹⁷
(Wherein R ¹⁷ represents an aryl group) or
(h) represents a C _1-6 alkyl group substituted with a C _3-7 cycloalkyl group),

(3)
-N (R ⁴ )-
(Where R ⁴ is
(a) -CO-N (R 15) (R 16)
Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an aryl group (the aryl group may be substituted with 1 to 3 C _1-8 alkyl groups), C _1-6 At least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may represent an alkyl group, or together with the nitrogen atom to which they are attached, form an indoline ring A 5- to 7-membered heterocyclic ring may be formed),
(b) —SO ₂ —N (R ¹⁵ ) (R ¹⁶ )
(Wherein R ¹⁵ and R ¹⁶ each independently represents an aryl group or a C _1-6 alkyl group),
(c) -CO-R ¹⁷
Wherein R ¹⁷ is an aryl group (the aryl group may be substituted with 1 to 3 substituents selected from the group consisting of a C _1-8 alkyl group and a C _1-4 alkoxy group); An aromatic heterocyclic group or a C _1-6 alkyl group (the C _1-6 alkyl group is an aryl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C _1-8 alkyl group) , An aromatic heterocyclic group, a C _1-4 alkoxy group that may be substituted with an aryl group, or an aryloxy group that may be substituted with 1 to 3 C _1-8 alkyl groups) ),
(d) -SO ₂ -R ¹⁷
(Wherein R ¹⁷ represents an aryl group) or
(e) represents an aryl group) or

(Four)
^{-N (R 8) -CO -,} - N (R 9) -CO-N (R 5) - or ^{-N (R 10) - (CH} 2) k -N (R 5) -
(Where
R ⁵ represents a C _1-6 alkyl group which may be substituted with a hydrogen atom or an aryl group,
R ⁸ represents a hydrogen atom or a C _1-6 alkyl group,
R ⁹ together with R ⁵

In which a and b each independently represent 0, 1 or 2;
k represents 0 or an integer of 1 to 4,
R ¹⁰ together with R ⁵

(Wherein, k1 and c each independently represent 0 or an integer of 1 to 4) or

(Wherein d and e each independently represent 0, 1 or 2)).
n is preferably 0 or an integer of 1 to 3.
p is preferably 0 or 1.
L is preferably the following (1) to (4).
(1)

(Where
R ²⁰ together with R ⁴

(In the formula, n1 and q each independently represent 0 or an integer of 1 to 4, and R ^{9 ′} represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a carboxy group, or a C _1-6 alkoxy group. Or)

(Wherein u and v each independently represent 0, 1 or 2),
R ²¹ represents a hydrogen atom)
(2)

(In the formula, E represents a phenyl group, a furyl group, an isoxazolyl group or a pyridyl group, and R ²² represents a hydrogen atom),
(3)

(Where
E represents a phenyl group;
R ²² is
(a) Together with R ⁴

(Wherein n2 and w each independently represents 0 or an integer of 1 to 3),
(b) Together with R ⁷

In which n4 and y each independently represents 0, 1 or 2;
(c) Together with R ⁷

In which n5 and z each independently represent 0 or 1, or
(d) Together with R ⁸

(Wherein n2 and w each independently represent 0 or an integer from 1 to 3)) or
(Four)

(Where
R ²⁰ together with R ⁴

(In the formula, n1 and q each independently represent 0 or an integer of 1 to 4, and R ^{9 ′} represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a carboxy group, or a C _1-6 alkoxy group. Form)
R ²¹ represents a hydrogen atom,
E represents a phenyl group, a furyl group, an isoxazolyl group or a pyridyl group;
R ²⁵ represents a hydrogen atom).

R represents —COO (R ¹⁹ ), —A ¹ —COO (R ¹⁹ ) or —O—A ¹ —COO (R ¹⁹ ).
In the formula, A ¹ represents a C _1-4 alkylene group, and R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group.

  B is a phenyl group or an aromatic heterocyclic group (the aromatic heterocyclic group is a thienyl group, thiazolyl group, pyrazolyl group, 1,3,4-thiadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, indolyl group) Group, a benzoimidazolyl group, a benzothiazolyl group and a benzoxazolyl group) are preferred.

  In the case of B, when V is = CH-, it is preferable that the substitution position of B is the 4-position or 5-position on the thiophene or furan ring formed by combining the V with W, and V is In the case where ═N—, the substitution position of B is preferably the 4-position on the thiazole or oxazole ring constituted by V together with W.

R ³ is preferably a hydrogen atom.

Y represents —C (R ¹³ ) (R ¹⁴ ) —N (R ¹² ) —, —C (R ¹³ ) (R ¹⁴ ) —O—, —N (R ¹¹ ) — or —O—.
(Wherein R ¹¹ represents a hydrogen atom or a C _1-8 alkyl group, R ¹² represents a hydrogen atom or a C _1-8 alkyl group, and R ¹³ and R ¹⁴ both represent a hydrogen atom).

s is preferably 0 or 1.
A is preferably a methylene group.

Y, s and A are preferably the following (1) or (2).
(1)
Y is —C (R ¹³ ) (R ¹⁴ ) —N (R ¹² ) — or —C (R ¹³ ) (R ¹⁴ ) —O—.
(Wherein R ¹² represents a hydrogen atom or a C _1-8 alkyl group, and R ¹³ and R ¹⁴ both represent a hydrogen atom),
And s is 0.
(2)
Y is —N (R ¹¹ ) — or —O—.
(Wherein R ¹¹ represents a hydrogen atom or a C _1-8 alkyl group),
S is 1, and A is a methylene group.

Z is
(a) a C _3-7 cycloalkyl group which may be substituted with 1 to 3 substituents selected from the group consisting of a halogen atom and a C _1-6 alkyl group,
(b) a halogen atom,
(c) a C _1-8 alkyl group,
(d) a C _1-4 haloalkyl group,
(e) a di (C _1-4 alkyl) amino group,
(f) a C _1-6 alkylthio group and
(g) An aryl group substituted with a substituent selected from the group consisting of C _1-4 alkylcarbonyl groups is preferred.

Z is a C _1-8 alkyl group (the C _1-8 alkyl group is isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group) More preferred is a phenyl group substituted with a group selected from the group consisting of a group and a 1-propylbutyl group.

  Z is particularly preferably a phenyl group substituted with a 1-ethylpropyl group or a 1-propylbutyl group.

In the general formula [I], particularly preferred embodiments are as follows.
V is particularly preferably ═N— or ═CH—.
W is particularly preferably -S-.
m is particularly preferably 1.
R ¹ and R ² are particularly preferably a hydrogen atom.

X, n, p and L are particularly preferably the following (1) to (7).
(1)
X is —N (R ⁴ ) —
(Wherein R ⁴ represents a C _1-6 alkyl group substituted with an aromatic heterocyclic group which may be substituted with 1 to 3 C _1-8 alkyl groups)
N is 1 and p is 0.

(2)
X is —N (R ⁴ ) —
(In the formula, R ⁴ represents —CO—N (R ¹⁵ ) (R ¹⁶ ).
Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an aryl group (the aryl group is a C _1-8 alkyl group, a C _1-4 alkoxy group, a carboxy group and a di (C _1-4 alkyl ) Which may be substituted with 1 to 3 substituents selected from the group consisting of amino groups), aromatic heterocyclic groups, C _1-6 alkyl groups (the C _1-6 alkyl group is an aryl group) Which may be substituted), or together with the nitrogen atom to which they are attached, may further contain at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A good 5- to 7-membered heterocycle may be formed)
A C _1-6 alkyl group substituted with
N is 1 and p is 0.

(3)
X is —N (R ⁴ ) —
(In the formula, R ⁴ represents —CO—N (R ¹⁵ ) (R ¹⁶ ).
Wherein R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an aryl group (the aryl group may be substituted with 1 to 3 C _1-8 alkyl groups), C _1-6 At least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may represent an alkyl group, or together with the nitrogen atom to which they are attached, form an indoline ring A 5- to 7-membered heterocycle which may contain
N is 1 and p is 0.

(Four)
X is —N (R ⁴ ) —, —SO ₂ —N (R ⁵ ) —, —CO—N (R ⁷ ) — or —O—.
(Wherein R ⁴ represents a hydrogen atom or a C _1-6 alkyl group, R ⁵ represents a hydrogen atom or a C _1-6 alkyl group, and R ⁷ represents a hydrogen atom or a C _1-6 alkyl group),
N is 0, p is 1, and L is

(In the formula, E represents a pyridyl group, and R ²² represents a hydrogen atom).

(Five)
X is —N (R ¹⁰ ) — (CH ₂ ) _k —N (R ⁵ ) —
(In the formula, k represents 0 or an integer of 1 to 4,
R ¹⁰ together with R ⁵

(Wherein k1 and c each independently represent 0 or an integer from 1 to 4)),
N is 0 or an integer from 1 to 4, p is 1, and L is

(In the formula, E represents a phenyl group, a furyl group, an isoxazolyl group or a pyridyl group, and R ²² represents a hydrogen atom).

(6)
X is —N (R ⁴ ) —
N is 0 or an integer from 1 to 4, p is 1, and L is

(Where
R ²⁰ together with R ⁴

(In the formula, n1 and q each independently represent 0 or an integer of 1 to 4, and R ^{9 ′} represents a hydrogen atom, a hydroxyl group, a C _1-6 alkyl group, a carboxy group, or a C _1-6 alkoxy group. Form)
R ²¹ represents a hydrogen atom,
E represents a phenyl group, a furyl group, an isoxazolyl group or a pyridyl group;
R ²⁵ represents a hydrogen atom).

(7)
X is —N (R ⁴ ) —
N is 0 or an integer from 1 to 3, p is 1, and L is

(Where
E represents a phenyl group;
R ²² together with R ⁴

(Wherein n2 and w each independently represent 0 or an integer from 1 to 3).

R is —COO (R ¹⁹ )
(Wherein R ¹⁹ represents a hydrogen atom or a C _1-4 alkyl group) is particularly preferred.

B is particularly preferably a phenyl group.
In the case of B, when V is = CH-, it is preferable that the substitution position of B is the 4-position or 5-position on the thiophene or furan ring formed by combining the V with W, and V is In the case where ═N—, it is particularly preferable that the substitution position of B is the 4-position on the thiazole or oxazole ring constituted by V together with W.

R ³ is particularly preferably a hydrogen atom.
Y, s and A are particularly preferably the following (1) or (2).
(1)
Y is —C (R ¹³ ) (R ¹⁴ ) —N (R ¹² ) — or —C (R ¹³ ) (R ¹⁴ ) —O—.
(Wherein R ¹² represents a hydrogen atom or a C _1-8 alkyl group, and R ¹³ and R ¹⁴ both represent a hydrogen atom),
And s is 0.

(2)
Y is —N (R ¹¹ ) — or —O—.
(Wherein R ¹¹ represents a hydrogen atom or a C _1-8 alkyl group),
S is 1, and A is a methylene group.

  Z is particularly preferably a phenyl group substituted with a 1-ethylpropyl group or a 1-propylbutyl group.

In the general formula [II], preferred embodiments are as follows.
V is preferably ═CH—.
W is preferably -S-.
Y ¹⁰⁰ is preferably —CH ₂ —.
R ¹⁰⁰ is preferably a hydroxyl group or a chlorine atom.
B is preferably a phenyl group.
B preferably has a substitution position of B at the 4-position on the thiophene ring formed by combining V and W together.
R ³ is preferably a hydrogen atom.

  The “pharmaceutically acceptable salt” may be any salt that forms a non-toxic salt with the compound represented by the above general formula [I]. For example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid Inorganic acids such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, benzylsulfonic acid, etc. Acid; or inorganic base such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammonium hydroxide; or methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, guanidine , Organic bases such as choline, cinchonine, N-methyl-D-glucamine; or lysine, Cytidine, it can be obtained by reacting arginine, with the amino acid alanine, and the like. In the present invention, a hydrate or hydrate or solvate of each compound is also included.

  In the compound represented by the above general formula [I], various isomers exist. For example, E isomer and Z isomer exist as geometric isomers, and when an asymmetric carbon atom exists, enantiomers and diastereomers as stereoisomers based on these exist. In some cases, tautomers may exist. Accordingly, the scope of the present invention includes all these isomers and mixtures thereof.

In the present invention, prodrugs and metabolites of the compound represented by the general formula [I] are also included.
A “prodrug” is a derivative of a compound of the present invention that has a group that can be chemically or metabolically decomposed and is restored to the original compound after administration to a living body and exhibits its original medicinal effect. Non-conforming complexes and salts.

For example, ester derivatives known as prodrugs in the pharmaceutical field can be used. Specific examples include ester derivatives in which the —COOR ⁷ moiety in R represents a group represented by the following formula.

  When the compound of the present invention is used as a pharmaceutical preparation, it is usually a pharmaceutically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer, emulsifier, fragrance, coloring. Agents, sweeteners, thickeners, flavoring agents, solubilizing agents, other additives, specifically water, vegetable oils, alcohols such as ethanol or benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, lactose, starch and other carbohydrates Tablets, pills, powders, granules, suppositories, injections, eye drops, solutions, capsules, troches, aerosols, elixirs, etc., mixed with magnesium stearate, talc, lanolin, petrolatum, etc. Can be administered systemically or locally, orally or parenterally, in the form of suspensions, emulsions, syrups, etc. .

  The dose of the compound of the present invention varies depending on age, weight, symptom, disease to be treated, administration method, etc., but is usually in the range of 1 mg to 1,000 mg per adult, once to several times a day. Is administered.

Compound [I] of the present invention is a PTP1B inhibitor, a receptor tyrosine kinase negative regulator inhibitor, a prophylactic or therapeutic agent for diabetes, diabetic complications (retinopathy, nephropathy, neuropathy, syndrome X or metabolic syndrome, imaginary Prevention or treatment of blood heart disease (myocardial infarction, angina, etc.) and stroke (cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, etc.), prevention or treatment of hyperlipidemia, prevention or treatment of obesity, nerve As a preventive or therapeutic agent for degenerative diseases (macular edema, macular degeneration etc.), a preventive or therapeutic agent for diseases mediated by PTP1B, mammals (human, mouse,
Rats, rabbits, dogs, cats, cows, pigs, monkeys, etc.).

The compound [I] of the present invention has an excellent selective PTP1B inhibitory action. “Excellent selective PTP1B inhibitory action” means that PTP1B inhibitory activity is stronger than other protein tyrosine phosphatases (eg, T-cell protein tyrosine phosphatase (TCPTP)) inhibitory activity. Specifically, for example, IC ₅₀ for PTP1B is that they exhibit low values of 1/10 or less than the IC ₅₀ for TCPTP, in which case, more preferably 1/60 or less, particularly preferably 1 / 300 or less. Therefore, the compound [I] of the present invention is a PTP1B inhibitor with few side effects, a receptor tyrosine kinase negative modulator inhibitor, a prophylactic or therapeutic agent for diabetes, a prophylactic or therapeutic agent for diabetic complications, and prevention of hyperlipidemia. Alternatively, it can be used as a therapeutic agent, a preventive or therapeutic agent for obesity, neurodegenerative diseases, etc., or a prophylactic or therapeutic agent for diseases mediated by PTP1B.

  “Receptor-type tyrosine kinase negative regulator inhibitor” refers to a factor that negatively regulates intracellular signal transduction originating from activation of receptor-type tyrosine kinase by binding to a ligand. Refers to a drug having an action to enhance For example, in the case of an insulin receptor which is one of receptor tyrosine kinases, the receptor is activated by binding to insulin, and the intracellular region of the receptor itself, IRS (insulin receptor substrate), etc. are phosphorylated. Signaling in cells that is oxidized and causes glucose uptake occurs, and a drug that inhibits a factor that negatively regulates such signaling is a receptor tyrosine kinase negative regulator inhibitor, and a typical example thereof is PTP1B. Inhibitors are mentioned. Receptor tyrosine kinase negative regulator inhibitors are different from existing insulin sensitivity enhancers (PPAR agonists such as thiazolidinedione derivatives). That is, as typified by PTP1B inhibitors, receptor tyrosine kinase negative regulator inhibitors act directly on intracellular signals elicited by insulin, and thus are sufficiently effective in the administration of existing insulin sensitivity enhancers. High efficacy can be expected even for non-obese mammals (non-obese diabetic patients, etc.), and side effects of existing insulin sensitivity enhancers can be expected.

  The compound [I] of the present invention is used in combination with other antidiabetic agents for the purpose of preventing or treating diabetes or diabetic complications (particularly, microvascular complications, ie, retinopathy, nephropathy, neuropathy, etc.). Can be used and coadministered to mammals. In the present invention, the “diabetes therapeutic agent” includes a therapeutic agent for diabetic complications (particularly, microvascular complications). In addition, the compound [I] of the present invention can be used in combination with other therapeutic drugs for hyperlipidemia for the purpose of preventing or treating hyperlipidemia, and can be administered in combination to mammals. Furthermore, the compound [I] of the present invention can be used in combination with other therapeutic agents for obesity and administered together to mammals for the purpose of preventing or treating obesity.

  Furthermore, the compound [I] of the present invention can be used for diabetic complications (particularly aortic complications, ie, syndrome X or metabolic syndrome, ischemic heart disease (myocardial infarction, angina pectoris, etc.)) and stroke (cerebral infarction, cerebral hemorrhage, For the purpose of prevention or treatment of subarachnoid hemorrhage, etc.), it is used in combination with diabetes, hyperlipidemia, obesity, hypertension and / or thrombosis, and mammals Can be administered in combination.

When used in combination with a therapeutic drug for diabetes, a therapeutic drug for hyperlipidemia, a therapeutic drug for obesity, a therapeutic drug for hypertension or a therapeutic drug for thrombosis (hereinafter referred to as a concomitant drug), the compound of the present invention is administered simultaneously with the concomitant drug. Alternatively, it may be administered at time intervals. When used in combination with a combination drug, it can be administered as a pharmaceutical composition containing the compound of the present invention and the combination drug. Alternatively, the pharmaceutical composition containing the compound of the present invention and the pharmaceutical composition containing the concomitant drug may be administered separately. The administration route of each pharmaceutical composition may be the same or different.

  When used in combination with a concomitant drug, when the concomitant drug has a mechanism of action different from that of the compound of the present invention (eg, insulin secretagogue, biguanide, α-glucosidase inhibitor, insulin preparation, insulin sensitivity enhancer, Receptor-type tyrosine kinase negative regulator inhibitors other than PTP1B inhibitors, etc.) not only provide additive preventive or therapeutic effects based on the actions of the compound of the present invention and the combination drug, but both It can also be expected to show the effect of prophylaxis or treatment amplified as a result of combining the actions. Therefore, in each case of the compound of the present invention and the concomitant drug, higher efficacy can be expected with a smaller dose compared to administration alone, and cannot be avoided when administered alone. It can also be expected to solve side effects. Accordingly, the compounds of the present invention can be administered once to several times a day at a dose ranging from 1 mg to 1,000 mg at a time, or may be administered at a lower dose. The concomitant medications can be administered at their usual dosage when they are used for the prevention or treatment of diabetes or diabetic complications, the prevention or treatment of hyperlipidemia, or the prevention or treatment of obesity, or A smaller dose may be administered.

Antidiabetic agents (ATP-dependent potassium (K (ATP)) channel inhibitors (sulfonylureas, sulfonamides, phenylalanine derivatives, etc.)), biguanides, α-glucosidase Inhibitors, insulin preparations, insulin analogs, insulin sensitivity enhancers (peroxisome proliferator-activated receptors (PPAR) γ agonists such as thiazolidinedione derivatives (glitazone)), IL-11, anti-CD25 (IL-2 receptor) Agents (monoclonal antibodies, etc.), angiotensin (AT1) antagonists, angiotensin converting enzyme (ACE) inhibitors, aldose reductase inhibitors, antioxidants (protein kinase activators / reverse transcription inhibitors), carnitine acetyltransferase stimulators, Antidepressants, glucocorticoids, retilins, radical formation agonists and transkets Hydrolase activator agents. Β3-adrenergic receptor agonist, insulin sensitivity enhancer, nuclear receptor modulator, peroxisome proliferator-activated receptor, PPARα agonist, PPARγ antagonist, PPARδ ligand (agonist or antagonist), fibrate, retinoid Drugs that act on receptors (such as retinoids), protein tyrosine phosphatase (PTP) inhibitors (other than the compound of the present invention), protein tyrosine phosphatase-1B (PTP1B) inhibitors (other than the compound of the present invention), T-cell protein tyrosine phosphatase ( (TCPTP) inhibitor (other than the compound of the present invention), leukocyte common antigen-related protein (LAR) inhibitor, SH2-containing inositol phosphatase 2 (SHIP2) inhibitor, c-JunNH2 terminal kinase (JNK) inhibitor, insulin receptor agonist, Insulin receptor kinase stimulant, insulin-like growth factor (IGF) -1 antagonist, dipeptidyl peptidase IV inhibitor, glucago -Like peptide 1 (GLP1) agonist, GLP1, leptin, ATP-dependent potassium channel activator; VPAC2 (receptor of vasoactive intestinal peptide (VIP)) agonist, P2Y agonist; β amyloid protein antagonist, apoptosis Inhibitors, TGR79 agonists, GPR40 agonists, sodium-glucose cotransporter inhibitors (SGLT-2 inhibitors, etc.), glycogen phosphorylase inhibitors, fructose-biphosphatase inhibitors, phosphoenolpyruvate carboxykinase (PEPCK) inhibition Agents, pyruvate dehydrogenase kinase inhibitors, glucose-6-phosphatase inhibitors, glycogen synthase kinase (GSK) -3 inhibitors, glucokinase activators, glucagon antagonists, signal transducers and transcription activators (STAT)- 3 Interrogators such as regulators, forkhead transcription factor (FOXO-1) inhibitors, IL-10 agonists and IL-4 agonists Kin (IL) agonist, IL-6 production inhibitor, tumor necrosis factor (TNF) -α production inhibitor, monocyte chemotactic factor protein (MCP) -1 expression inhibitor, adipocytokine modulator, plasminogen Activator inhibitor type 1 (PAI-1) production inhibitor, adiponectin production enhancer, adiponectin receptor agonist, adiponectin, resistin production inhibitor, resistin receptor antagonist, α2-adrenergic receptor antagonist, β2- Adrenergic receptor antagonist, 5-HT6 antagonist, serine carboxypeptidase inhibitor, ATP-binding cassette A1 (ABCA1) expression enhancer, retinoid X receptor (RXR) agonist, liver X receptor (LXR) ligand (agonist) Agent or antagonist), adipocyte fatty acid binding protein (FABP) (aP2) inhibitor, cholesterol antagonist, adenosine A2B antagonist, α1-adrenergic receptor agonist, α2-adrenergic receptor, carnitine O- Palmitoyltransferase inhibitor, AMP-activated protein kinase (AMPK) activator, glucose transporter (GLUT) -4 translocation activator, glucocorticoid receptor antagonist, glucocorticoid receptor modulator, 11β-hydroxysteroid dehydrogenase Inhibitor, growth hormone release inhibitor, somatostatin analog, somatostatin sst5 agonist, somatostatin sst2 agonist, growth hormone-releasing factor (GHRF), ghrelin production inhibitor, ghrelin receptor antagonist, kinase inhibitor, PTPN1 expression inhibitor Oligonucleotide, antioxidant, nitric oxide scavenger, free radical scavenger, heme oxygenase (HO) -1 inducer, EGFR (erbB1) inhibitor, phosphodiesterase III inhibitor, phosphodiesterase IV inhibitor, acetyl-CoA carboxylase (ACC ) Inhibitor, carnitine palmitoyl trans Cellulase (CPT) 1 inhibitor, glucose sensor activator, microsomal triglyceride transcription protein (MTP) inhibitor, diacylglycerol acyltransferase (DGAT) inhibitor, statin, cholesterol ester transfer protein (CETP) inhibitor, any other Glucose-reducing agent, anti-CD3 agent (monoclonal antibody, etc.), glutamate decarboxylase stimulator, combination of gastrin and epidermal growth factor (EGF), calcineurin inhibitor, antioxidant (metalloporphyrin, etc.), NAD + ADP-ribosyltransferase (poly (ADP-ribose) polymerase; PARP) inhibitor, immunostimulant, chemokine receptor agonist, chemokine receptor antagonist, vanadium complex, p38 protein kinase inhibitor, glycation end product (AGE) inhibitor (Maillard reaction inhibitor) ), Low molecular weight (LMW) heparin, inductive oxidation Nitrogen synthase inhibitor, antiplatelet-derived growth factor (PDGF) agent (monoclonal antibody, etc.), angiogenesis inhibitor (apoptosis inducing factor, endothelin antagonist (ETA), etc.), somatostatin sst2 antagonist, growth factor regulator, cell adhesion Inhibitor, amadorase inhibitor, transforming growth factor (TGF) -β receptor antagonist, TGF-β receptor signal inhibitor, TGF-β production inhibitor, anti-TGF-β antibody, anti-TGF-β receptor antibody Anti-lectin-like oxidized low density lipoprotein receptor (LOX) -1 agent (monoclonal antibody, etc.), Edge receptor antagonist, Edge receptor signal inhibitor, neurotrophic factor enhancer, neurotrophic agent, nerve growth factor ( NGF), NGF agonist, vascular endothelial growth factor (VEGF), neurotropin (NT) -3, NT-3 inducer, protein kinase (PK) Cβ inhibitor, γ-aminobutyric acid (GABA) mediated transport Drug, 5-HT reuptake inhibitor; 5-HT2A antagonist, Norepinephrine Reuptake inhibitors, drugs that act on vanilloid receptors, cannabinoid receptor agonists, IL-6, N-methyl-D-aspartate (NMDA) antagonists, prostaglandin E1, prostacyclin analogs, pyruvate dehydrogenase activity Agent, nitric oxide synthase (NOS) 3 expression enhancer, heat shock protein general agonist, sodium channel inhibitor, NAALADase inhibitor, general pump inhibitor, sonic hedgehog IgG, VEGF receptor antagonist, VEGF receptor Body signal inhibitor, pigment epithelium-derived factor (PEDF), anti-VEGF monoclonal antibody, matrix metalloproteinase inhibitor, methionine aminopeptidase-2 inhibitor, somatostatin sst1 agonist, tyrosine kinase inhibitor, epidermal growth factor antagonist, vitronectin ( αvβ3, αvβ5, etc.) antagonist, hypoxia-inducible factor (HIF) inhibitor, neuro Phosphorus-1 receptor antagonist, angiopoietin-2 receptor antagonist, angiopoietin -2 production inhibitor, angiopoietin-1 receptor agonist, angiopoietin -1 inducers like can be mentioned. For example, nateglinide, glimepiride, glibenclamide, gliclazide, acetohexamide, tolbutamide, glyclopyramide, tolazamide, glybsol, glipizide, gluconeuride, glyquidone, repaglinide, metformin hydrochloride, bformin hydrochloride, voglibose, acarbose, epalrestatone hydrochloride, insulin, miglitol hydrochloride, insulin Rosiglitazone maleate, chromium picolinate / biotin, V-411, recombinant human interleukin-11, dasiliximab (dacilitumab), losartan potassium, captopril, imidapril hydrochloride, α-lipoic acid, rebasecarnin hydrochloride (acetyl-L-carnitine) , Acetyl levocarnitine), captopril, retilin, verteporfin, benfotiamine and fluocinolone acetonide. It is used in combination as a pharmaceutical combination compound. Concomitant medications include: balaglitazone, riboglitazone, isaglitazone (netoglitazone), crypttrepine hydrochloride, triproamylin acetate (pramlintide), mitiglinide calcium hydrate, muraglitazar, tesaglitazar, oxeglitazar, insulin gluricin, insulin detemir , Hexyl insulin monoconjugate 2, Aerodose insulin inhaler, Air insulin, Technosphere / insulin, rDNA insulin, Other inhalation, Transpulmonary or oral human insulin, Exendin-4, Sulfostin, Liraglutide, Recombinant glucagon-like peptide- 1 (7-36) Amide (AC-2592), Dexlipatum, Cyclopostin R, Ramipril, Dehydrotramethenolic acid, Famoxine, Methoxime-3,4-defostatin, Demethylasteriki Non-B-1, Adiponectin (human), Saratinol, Reporin B, TAK-654, MBX-102, ADD-9918, ADD-9922, NN-304, NN-344, BIM-51077, LABI (NN-1215), SNAC / Insulin, LAF-237, 823093, 825964, 815541, P93 / 01, SSR-162329, LY-510929 (LY-929), LBL-752 (DRF-MDX8, DRF-4158), GW-677954, LY- 307161 SR, CJC-1131, SUN-E7001, ZP-10A (AVE-0010), MB-6322 (CS-917), BVT-2498, INGAP peptide, LY-818, TH-9507, ISIS-113715, SR- 58611, YM-178, SB-418790 (AZ-40140, GW-427353), N-5984, NN-2501, RF-1051, HMR-1426, NOX-700, ATL-962, 869682, R-1439, R -765, GW-501516, GI-181771, ST-1326, VDO-52, A-348441, BLX-1002, TLK-19781, ZYH-2, BLX-2001, NC-1567, R-1440, (FMS) 3-Insulin, Insulin chain B (9-23) peptide, Genapol stabilized insulin, Insulin transdermal agent, Metreleptin (recombinant methionyl human leptin), Pancreatic islet neogenesis therapy, NBI-6024, NN-344, O -346, DiaPep227 (AVE-027 7), TRX-4, rhGAD65, rhIGF-I (rhIGFBP-3), R-1524 (ISA-247, ISAtx-247), TRX-4-TolerMab, MnTE-2-Pyp5 + (AEOL-10113), CTCM- 226, irbesartan, telmisartan, candesartan cilexetil (hexetyl), platosartan, pyridoxamine (pyridoxylamine), lithospermic acid B magnesium (lysospermic acid B magnesium salt), sulodexide, aminoguanidine (pimagedin), pirfenidone, 1D11, CR- 002, T-8, (+)-A-127722 (A-147627, ABT-627), ED-4914, fidarestat, nefazodone hydrochloride, venlafaxine hydrochloride, pregabalin, ruboxistaurin mesylate, recombinant Human nerve growth factor, capsavanyl, dronabinol / cannabidiol, atexaquin alpha (interleukin-6), memantine hydrochloride, dexlipam, beraprost sodium, alimocromol maleate SX-3201 (AS-3201, SX-3030), TAK-428, QR-333, ruboxistaurin hydrochloride, octreotide acetate, aminoguanidine (pimagedin), pegaptanib octasodium, hyaluronidase, sescandelin, batimastat, recombinant Angiopoietin-1, LY-338522, BIM-23190, AdPEDF.11 (Ad (GV) PEDF.11D), VEGF Trap (VEG Trap (R1R2)), CVT-3634 and the like are also used. Preferably, other therapeutic agents for diabetes include insulin preparations such as insulin, glibenclamide, tolbutamide, nateglinide, metformin hydrochloride, voglibose and pioglitazone hydrochloride, insulin secretagogues, biguanides, α-glucosidase inhibitors and insulin sensitivity enhancers. included.

  Antihyperlipidemic drugs used as concomitant drugs include HMG-CoA reductase inhibitor (statin), fibrate, TNFSF6 expression inhibitor, HDL-cholesterol increase agent, apoA1 expression enhancer, SPP1 (osteopontin) expression inhibition Drugs, drugs that act on peroxisome proliferator-activated receptor (PPAR), PPARα agonists, lipase clarifier stimulants, cholesterol antagonists, platelet coagulation antagonists, antioxidants, cholesterol biosynthesis inhibitors, LDL-receptors Body upregulators, bile acid sequestrants, cholesterol absorption inhibitors and nicotinic acid. ACAT inhibitor, adenosine A1 agonist, apo B expression inhibitor, apo B secretion inhibitor, microsomal triglyceride transfer protein (MTP) inhibitor, HDL-cholesterol increase agent, cholesterol ester transfer protein (CETP) inhibitor, ileum Bile acid transporter inhibitor, insulin sensitivity enhancer, PPARα agonist, PPARγ agonist, PPARδ agonist, squalene synthase inhibitor, testosterone agonist, 11β-hydroxysteroid dehydrogenase inhibitor, 15-lipoxygenase inhibitor, 5-HT2 Antagonist, ABCA1 expression enhancer, ACAT inhibitor, retinoid RXR agonist, liver X receptor (LXR) agonist, acetyl-CoA carboxylase inhibitor, acetyl-CoA thiolase inhibitor, adenosine A2A agonist, adenylate cyclase activity Agent, adipocyte FABP (aP2) inhibitor, keratinocyte FABP (k-FABP) inhibitor, aldose Kutase inhibitor, angiogenesis inhibitor, anti-ICAM-1, anti-oxidant, VCAM-1 antagonist, anti-estrogen, estrogen agonist, lipid peroxidation inhibitor, apo B secretion inhibitor, apo B-100 reduction Agent, apoptosis inducer, apoptosis inhibitor, ATP citrate lyase inhibitor, β3-adrenergic receptor agonist, calcium channel inhibitor, carnitine O-palmitoyltransferase inhibitor, cholesterol esterase inhibitor, farnesoid X receptor (FXR) Drugs that act on drugs, farnesoid X receptor (FXR) agonists, drugs that act on thyroid hormone receptors, drugs that act on thyroid hormones, thyroid hormones, parathyroid hormone, farnesyltransferase inhibitors, glycogen phosphorylase alpha inhibitors, lanosterol 14α-demethylase inhibitor, lanosterol sinter Inhibitor, histamine H1 antagonist, nitric oxide synthase inhibitor, thromboxane A2 antagonist, triacylglycerol lipase inhibitor, α-glucosidase inhibitor, LDL-receptor upregulator, LYPLA1 expression inhibitor, nonsteroidal anti-inflammatory agent , PDGFR inhibitor, phospholipase A2 inhibitor, platelet activating factor (PAF) antagonist, potassium channel activator, prostaglandin, SCAP ligand, squalene epoxidase inhibitor, selective estrogen receptor modulator (SERM), Also included are sterol δ14-reductase inhibitors, vasopressin V1a antagonists and the like. For example, lovastatin, pravastatin (epeptatin) sodium, fluvastatin (fluindostatin) sodium, rosuvastatin calcium, atorvastatin calcium, simvastatin (simvinolin), pitavastatin (itavastatin, nisvastatin) calcium, lonifibrate (lonifibrate), binifibrate (Vinifibrate), clinofibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, bezafibrate, genfibrozil, acipimox, eicosapentaenoic acid (icosapentate, icopenate, icosapentate) ethyl ester, probucol, policosanol, resorcecolum hydrochloride hydrochloride Tyramine (cholestyramine resin), colestipol hydrochloride, kore Thymide (Koresuchiran), ezetimibe and niacin (nicotinic acid) is used in combination as a pharmaceutical combination with the compounds of the present invention. The concomitant drugs include pactimibe, eflutimibe, impritamide, large monolayer vesicles, campestanol ascorbyl phosphate, sitostanol ascorbyl phosphate, amlodipine besylate, GW-493838, RPR-749, BAY-13-9952, CP-346086 , BTG-511, JTT-705, LY-518674 (LY-674), ESP-31015 (ETC-1001), ETC-642 (ESP-24228, RLT), DRF-4832, S-8921, LY-510929 ( LY-929), GW-501516 (GW-516), FM-VP4, JTT-130, GW-590735, 641597, KRP-101, TAK-475, HE-2200 (3β, 7β, 17β-androstent triol) , D-003, PLT-732, NS-220, KS-01-019, AZD-7806, AZD-4619, AZD-6610, AZD-8294, ZYH-1, DRF-10945, SMP-797 etc. are also used The

Anti-obesity drugs used as concomitant medications include mazindol, lipase inhibitors, 5-HT / norepinephrine reuptake dual inhibitors, 5-HT reuptake inhibitors, herbal ephedrine and caffeine supplements, human chorionic gonads Stimulating hormones, adrenergic receptor agonists, methamphetamine, fentamine and amfepramon. In addition, drugs that act on cannabinoid receptors, cannabinoid CB1 receptor antagonists, cannabinoid CB1 receptor inverse agonists, ciliary neurotrophic factor (CNTF), growth hormone, growth hormone secretagogue, triacylglycerol lipase inhibitor ABCA1 expression enhancer, acetyl-CoA carboxylase inhibitor, adipocyte FABP (aP2) inhibitor, aldose reductase inhibitor, α-glucosidase inhibitor, α-mannosidase inhibitor, ATP citrate lyase inhibitor, adenosine A1 receptor Agonist, Serine carboxypeptidase inhibitor, 11β-hydroxysteroid dehydrogenase inhibitor, Drug acting on neuropeptide Y (NPY) receptor, Neuropeptide Y2 (NPY Y2) receptor agonist, Neuropeptide Y1 (NPY Y1) receptor Body antagonist, neuropeptide Y5 (NPY Y5) receptor antagonist, CCK antagonist, CCK1 (CCKA) agonist, CCK2 ( CCKB / gastrin antagonist, CRF1 antagonist, CRF2 agonist, melanin-concentrating hormone (MCH) receptor drug, MCH receptor antagonist, melanocortin receptor drug, melanocortin MC1 agonist, melanocortin MC3 agonist , Melanocortin MC4 agonist, melanocortin MC5 agonist, orexin receptor antagonist, orexin OX-1 antagonist, orexin OX-2 antagonist, neurotensin agonist, tachykinin NK2 antagonist, drug acting on thyroid hormone, thyroid gland Hormone receptor β agonist, galanin GAL1 antagonist, GHS (ghrelin) receptor inverse agonist, glucocorticoid receptor modulator, β2-adrenergic receptor agonist, β2-adrenergic receptor antagonist, β3-adrenergic receptor Agonist, α2-adrenergic receptor antagonist, MAO inhibitor, dopamine D1 antagonist, dopamine D5 antagonist, dopamine reuptake Inhibitors, dopamine-releasing drugs, norepinephrine reuptake inhibitors, drugs that act on 5-hydroxytryptamine receptors, 5-HT release stimulants, 5-HT1A antagonists, 5-HT1B agonists, bind to 5-HT2 receptors Drugs, 5-HT2A antagonists, 5-HT2B agonists, 5-HT2C (5-HT1C) agonists, drugs that bind to 5-HT6 receptors, 5-HT6 antagonists, drugs that bind to histamine H3 receptors , Histamine H3 antagonist, opioid antagonist, κ-opioid antagonist, estrogen agonist, selective estrogen receptor modulator (SERM), apo B secretion inhibitor, microsomal triglyceride transport protein (MTP) inhibitor, benzodiazepine, GABA (A) BZ site receptor agonist, CEBPA expression inhibitor oligonucleotide, SAPK1 (JNK) inhibitor, DAT inhibitor, NET inhibitor, SERT inhibitor, dipeptidyl peptidase IV inhibitor, glucagon-like peptide 1 (GLP- 1) Drugs that act on receptors Tripeptidyl peptidase II inhibitor, drugs acting on peroxisome proliferator-activated receptor (PPAR), PPARα agonist, PPARγ agonist, PPARγ antagonist, PPARγ partial agonist, PPARδ agonist, retinoid RXR agonist, retinoid RXR antagonist, fatty acid synthase inhibitor, glycogen phosphorylase inhibitor, HMG-CoA reductase inhibitor, protein tyrosine phosphatase (PTP) -1B inhibitor (other than the compound of the present invention), metalloporphyrin, nitric oxide synthase inhibitor, nonsteroidal anti-steroid Examples also include inflammatory drugs, phosphodiesterase III inhibitors, phosphodiesterase PDE3B inhibitors, SGLT-1 inhibitors, SGLT-2 inhibitors, sigma receptor ligands and the like. For example, mazindol, orlistat, sibutramine hydrochloride monohydrate, fluoxetine hydrochloride, chorionic gonadotropin (human), VNS therapy using the NCP system, metallaminol, d-methamphetamine hydrochloride, phentermine, amfepramon hydrochloride (diethylpropion), Benzphetamine hydrochloride and phendimetrazine tartrate are used in combination as a combination drug with the compound of the present invention. The concomitant drugs include rimonabant hydrochloride, SR-147778, CNTF (Ax15) (RG-228, RPN-228), polyethylene glycolated axocaine, GI-181771, SR-146131, SR-125180, AOD-9604, ATL -962, PYY3-36 (AC-162352), N-5984, L-796568, Garcinia acid ((-)-hydroxycitric acid), HMR-1426, P-57, 1954, Chromium picolinate / Isomerized linoleic acid S-2367, APD-356, BVT-5182, Ucn II, C-75, gAcrp30, KB-141, NLC-002, BLX-2002, P-64, T-71, etc. are also used.

Antihypertensive drugs used as concomitant drugs include thiazide, aldosterone antagonist, adrenergic neuron blocker, calcium channel blocker; dopamine D2 antagonist, β-adrenergic receptor antagonist, α2-adrenergic receptor agonist Agents, guanylate cyclase activator, β1-adrenergic receptor antagonist, α1-adrenergic receptor antagonist, antioxidant, angiotensin-I converting enzyme (ACE) inhibitor, Na ⁺ / H ⁺ exchange inhibitor, α -Adrenergic receptor antagonist, Nitric oxide donor, 5-HT2 antagonist, K (ATP) channel activator, Potassium-retaining diuretic prostaglandin synthase stimulator, Imidazoline I1 receptor agonist, Angiotensin AT1 antagonist , Dopamine D1 agonist, guanylate cyclase stimulant, endothelin ETA receptor antagonist, endothelin ETB receptor antagonist, NOS3 Potentiator, prostacyclin analog, prostaglandin, angiotensin II antagonist, electrolyte absorption agonist, nicotine antagonist, dopamine D2 agonist, prolactin inhibitor, platelet activator (PAF) antagonist, platelet coagulation antagonist, tumor Necrosis factor antagonists, Rho kinase inhibitors, PPARα agonists, AMPA receptor modulators; GABA (A) receptor antagonists and phosphodiesterase V (PDE5A) inhibitors. 5-HT1A receptor agonist, 5-HT1B antagonist, 5-HT2A antagonist, ACAT inhibitor, adenosine A1 agonist, adenosine A1 antagonist, adenosine A2A agonist, adenosine A2A antagonist, adenylate cyclase activity Agent, adrenergic neuron blocker, AGE inhibitor (Maillard reaction inhibitor), aldose reductase inhibitor, alkaloid, α-adrenergic receptor ligand, α1A-adrenergic receptor antagonist, α2-adrenergic receptor antagonist, β2-adrenergic receptor antagonist, β2-adrenergic receptor agonist, α-atrial natriuretic peptide, angiogenesis inhibitor, apoptosis inhibitor, angiotensin AT2 antagonist, angiotensin receptor antagonist, anti-inflammatory agent, free radical Capture agent, calcium channel activator, L-type calcium channel inhibitor, cAMP phosphodiesterase inhibitor Cannabinoid CB2 agonist, cannabinoid receptor agonist, vanilloid VR1 receptor agonist, chymase inhibitor, cyclooxygenase-2 inhibitor, dopamine autoreceptor agonist, dopamine receptor agonist, dopamine D1 agonist, dopamine D1 antagonist , Dopamine-β-monooxygenase inhibitor, endothelin receptor antagonist, endothelin receptor agonist, endothelin converting enzyme inhibitor, enkephalinase inhibitor, glycogen phosphorylase α inhibitor, growth hormone release inhibitor, somatostatin analog, histamine H1 agonists, histamine H1 antagonists, hypoxia-inducible factor 1-α (HIF-1α) inhibitors, drugs that act on imidazoline receptors, insulin analogs (zinc complexes), insulin sensitivity enhancers, {PPARα agonists} PPARγ agonist, insulin reducing agent, K (ATP) channel inhibitor, Pokishigenaze inhibitors, highly conductive BK (Ca) channel activating agent, Na ⁺ / K ⁺ -ATP-ase inhibitors, NADPH oxidase inhibitors, such as, neprilysin inhibitors, neuropeptide Y1 (NPY Y1) antagonists, neuropeptide Y4 ( NPY Y4) agonist, nitric acid, non-steroidal anti-inflammatory agent, protein kinase C (PKC) inhibitor, oligonucleotide, PDGFR inhibitor, phosphodiesterase inhibitor, phosphodiesterase I inhibitor, phosphodiesterase III inhibitor, phosphodiesterase IV inhibitor, potassium Channel activator, prostanoid IP agonist, prostanoid TP (thromboxane A2) antagonist, thromboxane synthase inhibitor, protease inhibitor, proteasome inhibitor, protein kinase C (PKC) inhibitor, renin inhibitor, σ Receptor antagonist, sodium channel blocker, thiazide, triglyceride reducing agent, Pressin antagonist, vasopressin V1a antagonists, vasopressin V2 antagonists such as are also mentioned. For example, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methycrothiazide, polythiazide, cypamide, cyclopenthiazide, bendroflumethiazide (bendrofluazide), spironolactone, epoxy mexrenone (eprerenone), guanethidine monosulfate, guanadrel sulfate, verapamil , Propranolol hydrochloride, alprenolol hydrochloride, pindolol, oxprenolol hydrochloride, timolol maleate, sotalol hydrochloride, acebutol hydrochloride, carteolol hydrochloride, mepindolol sulfate, arotinolol hydrochloride, indenolol hydrochloride, tartatrol hydrochloride, ceriprolol hydrochloride, hydrochloric acid Chirisolol, nebivolol, penbutol sulfate, nadolol, chloranolol hydrochloride, bevantol hydrochloride (bevantolol), black Gin, guanfacine hydrochloride, diltiazem hydrochloride, nicardipine hydrochloride, nitrendipine, felodipine, nilvadipine, nivadipine, nisoldipine, benidipine hydrochloride, amlodipine besylate, furanidipine hydrochloride (manidipine), rasidipine, isradipine, varnidipine hydrochloride (mepilodipine hydrochloride), ethanol efonidipine hydrochloride (Silnidipine), alanidipine, lercanidipine hydrochloride (masnidipine), azelnidipine, amlodipine, manidipine (furanidipine), sodium nitroprusside, atenolol, metoprolol tartrate, betaxolol hydrochloride, bopindolol, bisoprolol fumarate, esmolol hydrochloride, carvedilol hydrochloride, provezolol hydrochloride , Urapidil, indolamine hydrochloride, Zosin, terazosin hydrochloride, doxazosin mesylate, urapidil, nifedipine, captopril, enalapril maleate, lisinopril, perindopril, alacepril, ramipril, quinapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, cilazapril, fosinopril salt, fosinopril sodium Prill, spirapril, temocapril hydrochloride, moexipril hydrochloride, imidapril hydrochloride, zofenopril calcium, enalaprilate, zofenoprilate, amiloride hydrochloride, labetalol hydrochloride, nipradilol (nipradrol), phosphosidemine, ketanserin, pinacidil, cicletanol hydrochloride, cicletanadol hydrochloride Moxonidine hydrochloride hydrate, losartan potassium, valsartan, eprosartan mesylate Candesartan cilexetil (hexetyl), irbesartan, telmisartan, olmesartan medoxomil, fenoldopam mesylate, cadralazine, rilmenidine dihydrogen phosphate, bosentan, beraprost sodium, limaprost alphadex (α-cyclodextrin), uniprost (treprostinil sodium) , Iloprost (cyloprost), mecamylamine hydrochloride, metorgoline, guanabenz acetate, chloricchromene, fasudil, doconexent (docosahexaenoic acid), cyclothiazide, sildenafil citrate, chlorthalidone, quinetazone, indapamide, metolazone, phenoxybenzamine hydrochloride, methotyridine, diazododamine Torsemide), clopamide, hydralazine hydrochloride, reserpine and methyldopa It is used in combination as a pharmaceutical combination with the compounds of the present invention. Concomitant medications include omapatrilate, aradotril (aratriopril, fasidril), AVE-7688 (MDL-107688), 796406, remildipine, pranidipine, clevidipine, levamlodipine ((S) -amlodipine), ambrisentan , Sitaxsentan sodium, SPP-301 (R-639, RO-67-0565), TBC-3711, PMD-2850 (angiotensin vaccine), PMD-3117, binodenoson, alagebrium hydrochloride, SLV-306, aliskiren fumarate, NV-04, MC-4232, ENO, MDL-72832, BP-554, (+)-OSU-191 (OSU-191-(+), U-86192A), WAY-100339, QF-303B (QF-0303B ), QF-307B (QF-0307B), QF-311B (QF-0311B), Lindanserin (ZK-33839), AP-1067, AHR-16303B, QF-313B (QF-0313B), S-14280, S -35031, S-35120, PR-1173, RG-14718, CCPA, S-ENBA, Sch-59761, FR-166124, GU-285, MDL-101483, CVT-2995, CVT-3032, CVT-3033, 2HE -NECA (HENECA), CGS-21680, CGS-22492, CGS-22989, SHA-40, APEC, KF-17837, OPB-9195, Risospermic acid B magnesium salt (Risospermic acid B magnesium), 6-iodoamylolide, 6-protoberberine (PTB-6), CR-2991, HSR-175, CDRI-93 / 478, DC-015 (DC-028, DL-028A), BAM-2202, GB-67, YM-11133, Abbott-65265, SK & F-104856, MG-1, L-765314, KMUP-880602, A- 68828, YC-1, AB-47, C-112, uchibaprilate, FPL-63674 (FPL-63674XX, FPL-63547-dioic acid), FPL-66564, MDL-100173, MDL-27467A, glycopril, ROO 911, SQ -31440, DU-1777, S-nitrosocaptopril (SNOCAP), Y-23785, enalapril nitrate, moexiprilate
(RS-10029), Temocaprylate (RS-5139), CV-5975, Imidaprilate (6366 A), REV-6134, BW-B385C, CGS-26582, SA-6817, SA-7060, Sch-54470, S -Allyl mercaptocaptopril (CPSSA), RB-106, MDL-101628, Mixampril, Fasidotrirat (Alatrioprilate), BMS-182657, ER-32897, ER-32935, ER-40121, ER-40133 (E -4030), CGS-28106, CGS-30440, Sch-50690, A-81282 (Abbott-81282), A-81988, GA-0050, GA-0113, ZD-7155, RU-63455, RU-64276, RU -65868, Embusartan (Bay-10-6734), BIBS-39, BMS-180560, BMS-181688, BMS-184698, EXP-063, EXP6155, EXP-7711 (IMI), EXP-9270, S-8308, XD -937, XH-148, UP-221-78, UP-275-22, FI-6828K, FR-130739, FR-143187, FR-149581, LR-B / 087, RWJ-38970, RWJ-46458, WK -1492 (WK-1492.2K), KR-31080 (SK-1080), KT3-579, KT3-866, KW-3433, LY-285434, LY-301875, LY-302289, L-158338, L-158659, L-158978, L-159093, L-159689, L-161177, L-162154, L-162223, L-162234 , L-162393, L-162474, L-163313, L-163579, EMD-69943, EMD-90423, Tisartan (CGP-48369), Abitesartan (CGP-49870), CP-161418, CP-191166, PD- 123177 (EXP-655), PD-123319, PD-150304, SC-50560, SC-51316, SC-51757, SC-51895, SC-54628, SC-54629, U-97018, RWJ-47639, TH-142177 , CV-11194, 606A, TA-606, LCY-018, CR-3210, UP-275-13, UR-7198, UR-7280, WK-1260, CL-190133 (CL-332877, CL-190733, CL -190734), WAY-126227, YM-31472, EXP-408, XR-510, L-161021, L-162389, L-162441, L-162537, L-163007, L-163017, L-163958, BMS- 248360, DMP-811 (DuP-811, L-708404), SB-203220, LR-B / 057, L-159913, L-161816, sesamin, ferrinolol, PF-9104, TZC-1370, O-palmitoyl Chirisolol, BG6, TZC-8159, Y-22516, Orradipine hydrochloride (S-11568), PCA-50938, H-324 / 38, ZM-224832, HP-406, BMY-43011, SQ-32321, SQ-32547 , SQ-33351, Ernadipine, Rinkophylline, SUN-5647, VULM-999, DCDDP, Saganj , GR-60139, Goe-5584-A, silatiazem hydrobromide LR-A / 113), GS-386, solnidipine, MCF-1084, MCF-1113, dibudipine, deuterated nifedipine (ISA-1058), McN-6497 (RWJ-26902), CRL-41695, (4S)-(+)-AE0047, Y-24149, s-Petacin, NIP-101, UK-52831, UK-55444, UK-56593, UK-51656 , P-1268, BBR-2160, RS-88007, RS-5773, SL-85.1097, 83-0256, 83-0327, S-312 (83-
0312), MR-14134, AHR-12742, AHR-16462B, AHR-5360C (AHR-5360), BMY-20014, BMY-20064, BMY-42803, beloxane, rabedipine dilol B, rabedipine dilol A, FR- 172516, vanidipine dilol, xanthonolol, Z-6568, F-1850, Wy-27569, M-54033, HU-308, albanyl, BL-3875, BL-4027, TEI-E00548, rutaecarpine (lutecarpine), PD -139899, FPL-65447AA, Z-12571, Z-7760, (S) -Z-11410, FR-138104, MDL-43925, SK & F-102698, A-292438, A-306552, RPR-117820A, RPR-118031A , J-105510, J-105859, J-112287, BMS-182874, TBC-11040, TBC-11192, TBC-2576, TBC-3214, SB-247083, EMD-122946, EMD-94246, fundsentan potassium (CI -1034, PD-180988), PABSA, YM-62899, YM-91746, LU-302872 (BSF-420627, LU-420627), BMS-187308, IRL-3630, L-747844, RPR-111844, PD-163070 , PD-166309, PD-142893, A-192621, CGS-31398, IRL-1620, BQ-485, FR-901366 (WS-009A), KET-011, RES-701-1 (KF-20704), L -744453, L-74
9329, L-749805, IRL-1737, PD-155080, PD-156252, T-0115 (TA-0115), S-17162, WS-79089B (WS-79089-3, FR-901533), SM-19712, CGS-26303, CGS-26393, CGS-30084, CGS-34043, CGS-34225, CGS-34226, CGS-34753, CGS-35066, KC-12792, SQ-28603, CP-91149, BAY-41-2272, BAY-41-8543, BAY-58-2667, KMUP-1, Methylhistaprodifen, Suprahistaprodifen, S-23515, S-23757, LNP-509, LNP-911, Zn (car) 2Cl2, DRF- 4158 (DRF-MDX8, LBL-752), DY-9804, MJ-355, BPDZ-79, BPDZ-83, YM-099, Sarakalim (RS-91309), PNU-96293, NS-1608, CPU-23, PST-2107, Apocynin, CGS-24128, CGS-24592, CGS-25155, H-394 / 84, BIBO-3304, 1229U91 (GR-231118, BW-1229U91, GW-1229), RS-7897, C92-4609 (CAS-1609), CHF-2363 (SN011), PROLI / NO, FR-144420, GEA-3175, DS1, NOC-7, MAHMA MONOate, PF-9404, EDTA (edetic acid), AS-AT1R-ODN mRNA , NX-1975, 5E3623, Sch-51866, Sch-59498, LAS-31180, SK & F-94120, SK & F-95654, Win-63291, DMPPO, DF-100 (A80a), E-4 010, Zaprinast (M & B-22948), T-1032, Itpakalim hydrochloride, ZM-260384, RP-66784, S-0121, BMS-182264, KC-399, KC-515, SG-209, DY-9708, ER- 001533, RWJ-26629, U-94968, KI-4032, KRN-4884, KR-30818 (SKP-818), P-1060, LM-3339, MCC-134, AL-0671, AL-0670, Y-26763 , PC-286, TAK-636, Geoclein, UR-8081, UR-8218, UR-8225, UR-8267, CL-188294, LP-805, KMUP-880708, Cromakalim, BW-68C, FR-181157, FR -181877, ER-017996, PSI, MDL-29152, A-62198, A-65317, A-68064, A-82110, A-70461, ICI-219623, MDL-73323, MDL-74147, S-2864, BW -175, BILA-2157, SQ-30774, SQ-31844, SQ-33800, JTP-2438, JTP-2724, JTP-3072, JTP-4129, JTV-505 (JTP-4761), KRI-1177, KRI- 1314, CGP-44099A, CGP-54061, CGP-55128A, CGP-56346A, CGP-56962A, CGP-62198A, CP-108671, CP-71362, PD-132002, SC-46944, SC-56525, U-77436, Ro-44-9375, Ro-66-1132 (RO-0661132, RO-X1), RO-X2, SPP-600, CL-331049, WAY-121604, YM-21095, YM-26365, Hydroxy Asujiru, Y-30141, H-1152 (HMN-1152), CNS-1307, Ono-1505, JTV-605, YM-176770, JNJ-17079166, also like FR-161282 are used.

  Examples of the therapeutic agent for thrombosis used as a concomitant drug include heparin preparation, low molecular weight heparin, heparin analog, anticoagulant, thrombin inhibitor, antithrombin preparation, antiplatelet agent, thrombolytic agent and the like. For example, heparin calcium, heparin sodium, dalteparin sodium, parnaparin sodium, leviparin sodium, danaparoid sodium, warfarin potassium, argatroban, gabexate mesylate, nafamostat mesylate, human antithrombin III, aspirin, dipyridamole, ticlopidine hydrochloride , Cilostazol, limaprost alfadex, sodium ozagrel, sarpogrelate hydrochloride, ethyl icosapentate, beraprost sodium, urokinase, tysokinase, alteplase, nasarplase, nateplase, monteplase, pamiteplase, batroxobin, sodium citrate, protein C, etc. in combination with the compound of the present invention Used in combination as a medicine.

  Next, the example of the manufacturing method of the compound used in order to implement this invention is demonstrated. However, the manufacturing method of this invention compound is not limited to these.

  Even if there is no description in this production method, the production may be carried out efficiently by devising such as introducing a protecting group into the functional group and performing deprotection in a post-process as necessary, or changing the order of each production method and step.

  In each step, the treatment after the reaction may be performed by a usual method such as extraction, washing, concentration, filtration, pH adjustment, etc., and isolation and purification may be performed by crystallization, recrystallization, silica gel chromatography, A commonly used method such as preparative HPLC may be selected as appropriate, and may be performed in combination.

Manufacturing method 1
In this production method, m is 1, R ¹ and R ² are each a hydrogen atom, and X is —N (R ⁴ ) —, —N (R ⁵ ) —CO—O—, —O— or —S. This is a method for producing the compound [I].

(Wherein Q ¹ represents a general leaving group (for example, a halogen atom (bromine atom, iodine atom, chlorine atom, etc.), mesyloxy group, tosyloxy group, trifluoromethanesulfonyloxy group, etc.), and R ^X represents A protective group for a hydroxyl group (for example, tert-butyldimethylsilyl group, benzoyl group, etc.), and X ′ is —N (R ⁴ ) —, —N (R ⁵ ) —CO—O—, —O— or -S- (wherein each symbol is as defined above), and the other symbols are as defined above.)

Process 1
Compound [4] can be obtained by reducing compound [1] in a solvent using a conventional reducing agent. Examples of the solvent include alcohols (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), toluene, etc., or a mixed solvent thereof. Examples of the reducing agent include sodium borohydride, lithium borohydride, diborane, lithium aluminum hydride and the like. The reaction can be carried out under cooling to heating.

Process 2
Compound [4] can be obtained by reacting compound [2] with paraformaldehyde in a solvent in the presence of a base to effect hydroxymethylation. Examples of the solvent include toluene, ether solvents (tetrahydrofuran, diethyl ether, etc.), and mixed solvents thereof. Examples of the base include bases formed using alkyllithium (n-butyllithium, sec-butyllithium, tert-butyllithium, etc.) and 2,2,6,6-tetramethylpiperidine, or lithium diisopropylamine. It is done. The reaction can be carried out under cooling.

Process 3
Compound [4] can be obtained by deprotecting R ^X of compound [3] according to a conventional method. For example, when R ^X is a benzoyl group, the target product can be obtained by carrying out the same reaction as that exemplified in Step 30 of Production Method 19.

Process 4
Compound [5] can be obtained by substituting the hydroxyl group of compound [4] with a general leaving group in the same manner as in Step 18 in Production Method 10.

Process 5
Compound [I] -1 can be obtained by reacting compound [5] with compound [6] in a solvent in the presence of a base, in the presence or absence of a catalyst. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, alcohol solvents (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform) , Dichloromethane, etc.) or a mixed solvent thereof. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. Examples of the catalyst include potassium iodide, quaternary ammonium salts (tetrabutylammonium iodide, tetrabutylammonium bromide, etc.) and the like. The reaction can be carried out under cooling to heating.

Manufacturing method 2
This production method is a method for producing a compound in which X ′ is —N (R ⁴ ) — among the compounds [6] used in Step 5 in Production Method 1.

(In the formula, Q ² represents a general leaving group as described in Production Method 1, and the other symbols are as defined above.)
Step 6
Compound [9] can be obtained by reacting compound [7] with compound [8] in a solvent in the presence of a base, in the presence or absence of a catalyst. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, alcohol solvents (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform) , Dichloromethane, etc.) or a mixed solvent thereof. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. Examples of the catalyst include potassium iodide, quaternary ammonium salts (tetrabutylammonium iodide, tetrabutylammonium bromide, etc.) and the like. The reaction can be carried out under cooling to heating.

Manufacturing method 3
This production method is a compound in which V is = CH-, W is -S-, m is 1, R ¹ and R ² are each a hydrogen atom, and X is -N (R ⁴ )-. This is a method for producing [I].

（式中、各記号は前記定義の通りである。）

(In the formula, each symbol is as defined above.)

Step 7
Compound [I] -2 can be obtained by reacting compound [1] with compound [10] in a solvent in the presence of a reducing agent, in the presence or absence of a base. Solvents include N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, 1,2-dichloroethane, etc.) , Alcohol solvents (methanol, ethanol, etc.), acetic acid, etc., or a mixed solvent thereof. Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. Examples of the base include organic bases such as pyridine. The reaction temperature is preferably 0 ° C to 80 ° C.

Manufacturing method 4
This production process is a V is = CH-, W is -S-, m is 0, is a method of X to produce a -N (R ⁸⁾ -CO-, compound [I].

(In the formula, each symbol is as defined above.)
Process 8
Compound [11] can be obtained by subjecting compound [1] to an aldehyde oxidation method using a normal oxidizing agent in a solvent. Examples of the solvent include alcohols (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), acetone, acetic acid, water, etc., or a mixed solvent thereof. Examples of oxidizing agents include sodium chlorite (add chlorine scavenger (sulfamic acid etc. if necessary)), sodium hypochlorite, potassium permanganate, sodium chromate, silver nitrate, silver oxide, 2,2, Examples include 6,6-tetramethylpiperidine-N-oxide. The reaction can be carried out under cooling to heating.

Step 9
Compound [I] -3 can be obtained by subjecting compound [11] to amide condensation with compound [12] (which can be obtained by the same method as for obtaining compound [9] in production method 2). Amide condensation can be performed according to a conventional method. For example, in a solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, diphenylphosphoryl A method of condensing in the presence of a condensing agent such as azide and in the presence or absence of N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like can be mentioned. The reaction temperature is preferably 0 ° C to 100 ° C.

Manufacturing method 5
This production method is a method for producing a compound [I] in which m is 1, R ¹ and R ² are each a hydrogen atom, and X is —N (R ⁴ ) —.

(Wherein Q ³ represents a general leaving group as described in production method 1, and the other symbols are as defined above.)
Step 10
Compound [I] -4 (which can be obtained by the same method as that for obtaining Compound [I] -1 in Production Method 1) is reacted with Compound [13] in a solvent in the presence or absence of a base. Thus, compound [I] -5 can be obtained. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, etc.), etc., or a mixture thereof A solvent is mentioned. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. The reaction can be carried out under cooling to heating.

Step 11
Compound [I] -6 can be obtained by reacting compound [I] -4 with compound [14] in a solvent in the presence or absence of a base. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, etc.), etc., or a mixture thereof A solvent is mentioned. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. The reaction can be carried out under cooling to heating.

Manufacturing method 6
This production method is a method for producing a compound [I] wherein m is 1 or 2, and X is —N (R ⁴ ) —.

(Wherein m ′ represents 1 or 2, Q ⁴ represents a general leaving group as described in Production Method 1, and R ^Y represents an amine protecting group such as a tert-butoxycarbonyl group or a benzyloxycarbonyl group. The other symbols are as defined above.)
Step 12
Compound [16] can be obtained by deprotecting R ^Y of compound [15]. Deprotection can be performed according to a conventional method. For example, when R ^Y is a tert-butoxycarbonyl group, a method of reacting with hydrogen chloride in a solvent such as dioxane can be mentioned. The reaction temperature is preferably 0 ° C. to room temperature.

Step 13
Compound [I] -7 can be obtained by reacting compound [16] with compound [17] in the presence of a base in a solvent. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, etc.), etc., or a mixture thereof A solvent is mentioned. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. The reaction can be carried out under cooling to heating.

Manufacturing method 7
This production method is a method for producing a compound [I] in which m is 1 or 2 and X is —SO ₂ —N (R ⁵ ) —.

(In the formula, Q ⁵ represents a halogen atom (bromine atom, iodine atom, fluorine atom, chlorine atom, etc.), and other symbols are as defined above.)
Step 14
Compound [I] -8 is obtained by reacting compound [18] (which can be obtained by the same method as that for obtaining compound [16] in production method 6) with compound [19] in a solvent in the presence of a base. Can be obtained. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, etc.), etc., or a mixture thereof A solvent is mentioned. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. The reaction can be carried out at room temperature or under heating.

Manufacturing method 8
This production method is a method for producing a compound [I] in which m is 1 or 2 and X is —CO—N (R ⁷ ) —.

(Wherein R ^D represents a formyl group substituted with a carboxy group or a halogen atom (bromine atom, iodine atom, fluorine atom, chlorine atom, etc., and other symbols are as defined above). Step 15
Compound [I] -9 can be obtained by subjecting compound [20] (which can be obtained by the same method as that for obtaining compound [16] in production method 6) to amide condensation with compound [21]. Amide condensation can be performed according to a conventional method. For example, when R ^D is a carboxy group, dicyclohexylcarbodiimide, 1-ethyl-3- (3- (3-), N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene and the like. Examples thereof include a method of condensation in the presence of a condensing agent such as (dimethylaminopropyl) carbodiimide / hydrochloride, diphenylphosphoryl azide, and in the presence or absence of N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like. The reaction can be carried out under cooling to heating. On the other hand, when R ^D is a formyl group substituted with a halogen atom, for example, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene, water, etc., or a mixed solvent thereof And a method of condensation in the presence of a base such as an inorganic base (sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, etc.) or an organic base (triethylamine, diisopropylethylamine, pyridine, etc.). The reaction can be carried out under cooling to heating.

Manufacturing method 9
This production method is a method for producing a compound [I] wherein m is 1 or 2, and X is —NH—CO—N (R ⁵ ) —.

(In the formula, each symbol is as defined above.)
Step 16
Compound [I] -10 can be obtained by reacting compound [18] with compound [22] in a solvent in the presence or absence of a base. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, etc.), etc., or a mixture thereof A solvent is mentioned. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. The reaction can be carried out under cooling to heating.

Manufacturing method 10
This production method is used in the compound [I], the compound [1] used in the production methods 1, 3 and 4, the compound [2] used in the production method 1, the compound [3] used in the production method 1, or the production method 6. among the compounds [15], Y is ^{_{-CH 2 -N (R 12) -}} , - a method of manufacturing a CH ₂ -O- or -CH ₂ -S-, compound.

(Where R ^M is

(Wherein each symbol is as defined above), R ^B represents a carboxy group, a carboxy group substituted with an alkyl group (methyl group, ethyl group, etc.) or a formyl group, and Q ⁶ represents Production Method 1 And Y ′ represents —N (R ¹² ) —, —O— or —S— (wherein each symbol is as defined above), and other symbols Is as defined above. )

Step 17
Compound [24] can be obtained by activating the compound [23] in a solvent with an activator if necessary and then using a conventional reducing method using a reducing agent. Examples of the solvent include alcohols (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), toluene, etc., or a mixed solvent thereof. Examples of the reducing agent include sodium borohydride, lithium borohydride, diborane, lithium aluminum hydride and the like. The active agents, for example, when R ^B is carboxy groups include carbonyldiimidazole, and the like. The reaction can be carried out under cooling to heating.

Step 18
Compound [25] can be obtained by replacing the hydroxyl group of compound [24] with a general leaving group according to a conventional method. For example, conversion to a mesyloxy group, tosyloxy group and the like can be performed by using such a sulfonyl chloride in a solvent in the presence of an organic base. Solvents include toluene, ethyl acetate, halogen solvents (chloroform, dichloromethane, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), acetonitrile, N, N-dimethylformamide, or a mixed solvent thereof, and the organic base is pyridine. , Triethylamine, diisopropylethylamine and the like. The reaction can be carried out under cooling to heating. On the other hand, the conversion to a chlorine atom can be carried out by using thionyl chloride without solvent or in a solvent. Examples of the solvent include toluene, ethyl acetate, halogen-based solvents (chloroform, dichloromethane, etc.), ether-based solvents (tetrahydrofuran, dioxane, etc.), or a mixed solvent thereof, and N, N-dimethylformamide may be added as a catalyst. I do not care. The reaction can be carried out under cooling to heating. Further, the conversion to a chlorine atom can also be carried out by further reaction with an alkali metal chloride (such as lithium chloride) or a quaternary ammonium chloride after conversion to a mesyloxy group, tosyloxy group or the like. Examples of the solvent include acetonitrile, N, N-dimethylformamide and the like. The reaction can be carried out under cooling to heating.

Step 19
Compound [27] can be obtained by reacting compound [25] with compound [26] in a solvent in the presence of a base and in the presence or absence of a catalyst. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, alcohol solvents (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform) , Dichloromethane, etc.) or a mixed solvent thereof. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine, diisopropylethylamine and potassium tert-butoxide. Examples of the catalyst include potassium iodide, quaternary ammonium salts (tetrabutylammonium iodide, tetrabutylammonium bromide, etc.) and the like. The reaction can be carried out at room temperature or under heating.

Manufacturing method 11
This production method is used in the compound [I], the compound [1] used in the production methods 1, 3 and 4, the compound [2] used in the production method 1, the compound [3] used in the production method 1, or the production method 6. This is a method for producing a compound of the compound [15] wherein Y is —CO—N (R ¹² ) —.

(In the formula, each symbol is as defined above.)
Step 20
Compound [30] can be obtained by subjecting compound [28] to amide condensation with compound [29]. Amide condensation can be performed according to a conventional method. For example, in a solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride, diphenylphosphoryl A method of condensing in the presence of a condensing agent such as azide and in the presence or absence of N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like can be mentioned. The reaction temperature is preferably 0 ° C to 100 ° C.

Manufacturing method 12
This production method is used in the compound [I], the compound [1] used in the production methods 1, 3 and 4, the compound [2] used in the production method 1, the compound [3] used in the production method 1, or the production method 6. Among the compounds [15], Y is a method for producing a compound in which —N (R ¹¹ ) —, —O— or —S— is produced.

(In the formula, Q ⁷ represents a general leaving group as in Production Method 1, Y ″ represents —N (R ¹¹ ) —, —O— or —S—, and the other symbols are as defined above. Street.)
Step 21
Compound [33] can be obtained by reacting compound [31] with compound [32] in a solvent in the presence of a base, in the presence or absence of a catalyst. As the solvent, N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, alcohol solvents (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform) , Dichloromethane, etc.) or a mixed solvent thereof. Examples of the base include inorganic bases such as potassium carbonate and sodium carbonate, and organic bases such as triethylamine and diisopropylethylamine. Examples of the catalyst include potassium iodide, quaternary ammonium salts (tetrabutylammonium iodide, tetrabutylammonium bromide, etc.) and the like. The reaction can be carried out at room temperature or under heating.

Manufacturing method 13
This production method is used in the compound [I], the compound [1] used in the production methods 1, 3 and 4, the compound [2] used in the production method 1, the compound [3] used in the production method 1, or the production method 6. Among the compounds [15], Y is —N (R ¹¹ ) —, s is 1, and A is a methylene group.

(In the formula, each symbol is as defined above.)
Step 22
Compound [36] can be obtained by reacting compound [34] with compound [35] in the presence of a reducing agent in a solvent. Examples of the solvent include N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, etc.), acetic acid, and the like. The mixed solvent is mentioned. Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride and the like. The reaction temperature is preferably 0 ° C to 80 ° C.

Manufacturing method 14
This production method is used in the compound [I], the compound [1] used in the production methods 1, 3 and 4, the compound [2] used in the production method 1, the compound [3] used in the production method 1, or the production method 6. In the compound [15], Y is a method for producing a compound wherein —N (R ¹² ) —CO—.

(Wherein R ^C represents a formyl group substituted with a carboxy group or a halogen atom (bromine atom, iodine atom, fluorine atom, chlorine atom, etc., and other symbols are as defined above). Step 23
Compound [39] can be obtained by subjecting compound [37] to amide condensation with compound [38]. Amide condensation can be performed according to a conventional method. For example, in the case where R ^C is a carboxy group, dicyclohexylcarbodiimide, 1-ethyl-3- (3- (3- (3-aminobenzene), in a solvent such as N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene and the like. Examples of the method include condensation in the presence of a condensing agent such as (dimethylaminopropyl) carbodiimide / hydrochloride, diphenylphosphoryl azide, and in the presence or absence of N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like. On the other hand, when R ^C is a formyl group substituted with a halogen atom, for example, N, N-dimethylformamide, acetonitrile, tetrahydrofuran, chloroform, ethyl acetate, methylene chloride, toluene, water, or a mixed solvent thereof And a method of condensation in the presence of a base such as an inorganic base (sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, sodium hydroxide, etc.) or an organic base (triethylamine, diisopropylethylamine, pyridine, etc.). The reaction can be carried out under cooling to heating.

Manufacturing method 15
This production method is used in the compound [I], the compound [1] used in the production methods 1, 3 and 4, the compound [2] used in the production method 1, the compound [3] used in the production method 1, or the production method 6. Among the compounds [15], Y is —N (R ¹¹ ) —, s is 1, and A is a methylene group.

(In the formula, Q ⁸ represents a general leaving group as in Production Method 1, and the other symbols are as defined above.)
Step 24
Compound [41] can be obtained by introducing a formyl group into compound [40] according to a conventional method. For example, when Z is an aryl group or an aromatic heterocyclic group (the aryl group or aromatic heterocyclic group may be substituted as described above), the compound is present in a solvent in the presence of Lewis acid. Compound [41] can be synthesized by reacting [40] with dichloromethyl methyl ether and hydrolyzing the resulting methoxychloromethyl compound. Examples of the solvent include halogen solvents (chloroform, dichloromethane, etc.). Examples of the Lewis acid include aluminum chloride, titanium tetrachloride, and tin tetrachloride. The reaction can be carried out under cooling to room temperature.

Step 25
Compound [43] can be obtained by reacting compound [41] with compound [42] in the presence of a reducing agent in a solvent. Solvents include N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, toluene, ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane, 1,2-dichloroethane, etc.) , Alcohol solvents (methanol, ethanol, etc.), acetic acid, etc., or a mixed solvent thereof. Examples of the reducing agent include sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like. The reaction temperature is preferably 0 ° C to 80 ° C.

Step 26
Compound [45] can be obtained by reacting compound [43] with compound [44] in a solvent in the presence of a base and in the presence of a catalyst. Examples of the solvent include toluene, xylene, ether solvents (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) and the like, or a mixed solvent thereof. Examples of the base include cesium carbonate, sodium tert-butoxide, tripotassium phosphate and the like. Examples of the catalyst include palladium complexes (for example, complexes formed using palladium acetate and (R)-(+)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl). . The reaction can be carried out at room temperature or under heating.

Manufacturing method 16
This production method is the compound [I] or the compound [3] used in the production method 1, the compound [15] used in the production method 6, the compound [23] used in the production method 10, and the compound [28] used in the production method 11. Of the compound [31] used in the production method 12, the compound [34] used in the production method 13, the compound [37] used in the production method 14 or the compound [44] used in the production method 15, V is ═N—. , W is -S-, and the compound in which the substitution position of B on the thiazole ring constituted by V and W is 4-position is produced.

(Where ^RN is

Wherein each symbol is as defined above, and R ^P is

(Wherein each symbol is as defined above), Q ⁹ represents a general leaving group as described in Production Method 1, and the other symbols are as defined above. )
Step 27
Compound [48] can be obtained by reacting compound [46] with compound [47] in a solvent in the presence or absence of a base. Solvents include N, N-dimethylacetamide, N, N-dimethylformamide, acetonitrile, ethyl acetate, alcohol solvents (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, dioxane, etc.), halogen solvents (chloroform, dichloromethane). Etc.) or a mixed solvent thereof. Examples of the base include inorganic bases such as sodium hydrogen carbonate, and organic bases such as diisopropylethylamine. The reaction can be carried out under cooling to heating.

Manufacturing method 17
This production method is the compound [I] or the compound [3] used in the production method 1, the compound [15] used in the production method 6, the compound [23] used in the production method 10, and the compound [28] used in the production method 11. Of the compound [31] used in the production method 12, the compound [34] used in the production method 13, the compound [37] used in the production method 14 or the compound [44] used in the production method 15, V is ═N—. , W is —O—, and the compound in which the substitution position of B on the oxazole ring constituted by V and W is 4-position is produced.

(In the formula, each symbol is as defined above.)
Step 28
Compound [49] can be obtained by reacting compound [49] with compound [47] without solvent or in a solvent. Examples of the solvent include acetonitrile, alcohols (methanol, ethanol, isopropyl alcohol, etc.), xylene, toluene, and the like, or a mixed solvent thereof. The reaction can be carried out under heating.

Manufacturing method 18
This production method is used in the compound [I], the compound [1] used in the production methods 1, 3 and 4, the compound [15] used in the production method 6, the compound [23] used in the production method 10, and the production method 11. Of the compound [28], the compound [31] used in the production method 12, the compound [34] used in the production method 13, the compound [37] used in the production method 14 or the compound [44] used in the production method 15, V = This is a process for producing compound [I] wherein CH— and W is —S—.

(Where ^RQ is

(Wherein each symbol is as defined above), Q ¹⁰ represents a general leaving group as in Production Method 1, R ^A represents a boronic acid group (—B (OH) ₂ ), Other symbols are as defined above. )
Step 29
Compound [55] is obtained by reacting Compound [51] with Compound [52] or Compound [53] with Compound [54] in a solvent in the presence of a base and in the presence of a catalyst. Can do. Examples of the solvent include N, N-dimethylformamide, acetonitrile, alcohol solvents (methanol, ethanol, etc.), ether solvents (tetrahydrofuran, 1,2-dimethoxyethane, etc.), toluene, water, etc., or a mixed solvent thereof. It is done. Examples of the base include inorganic bases such as potassium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and potassium phosphate, and organic bases such as triethylamine. Examples of the catalyst include palladium catalysts (tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, palladium acetate-triphenylphosphine, etc.) and the like. The reaction can be carried out at room temperature or under heating.

Manufacturing method 19
This production method is a method for producing compound [I] in which R is —COOH, —A ¹ —COOH, or —O—A ¹ —COOH.

(In the formula, R ′ represents —COOH, —A ¹ —COOH or —O—A ¹ —COOH, and other symbols are as defined above.)
Step 30
When R ¹⁹ in R of compound [I] -11 is a C _1-4 alkyl group, compound [I] -12 can be obtained by deprotection according to a conventional method leading to carboxylic acid. For example, the method of hydrolyzing in the presence of a base in a solvent is mentioned. Examples of the solvent include alcohols (methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, water and the like, or a mixed solvent thereof. Examples of the base include alkali metal hydroxides such as sodium hydroxide, potassium carbonate, sodium carbonate and the like. The reaction can be carried out under cooling to heating.
Furthermore, the compound [I] obtained by the said manufacturing method can add the acid or base in a solvent and stir, and can obtain the pharmaceutically acceptable salt of compound [I]. Examples of the solvent include 2-butanone, acetone, tetrahydrofuran, ethyl acetate, methanol, ethanol, water, hexane, or a mixed solvent thereof. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, malonic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, and benzenesulfonic acid. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and calcium hydroxide, and organic bases such as triethylamine, ethylenediamine, tris (hydroxymethyl) aminomethane, and N-methyl-D-glucamine. The reaction can be carried out at room temperature.

  Crystals are precipitated by dissolving or suspending the compound [I] obtained above or a pharmaceutically acceptable salt thereof in a solvent at room temperature or under heating, and stirring or standing at 0 ° C. to 150 ° C. The compound [I] or a pharmaceutically acceptable salt thereof can be obtained by filtration after adding a poor solvent for the compound or a salt thereof as necessary under cooling to room temperature. Examples of the solvent include 2-butanone, acetone, tetrahydrofuran, ethyl acetate, methanol, ethanol, water, hexane, or a mixed solvent thereof.

  In addition, the manufacturing method described in this specification is an example of the manufacturing method of this invention compound, It manufactures also about compounds other than having demonstrated above by combining a well-known normal method in the field | area of organic synthetic chemistry. Can do.

  Next, the compound represented by the general formula [I] and the production method thereof according to the present invention will be specifically described with reference to Examples, but the present invention is not limited to these Examples.

Example 1-1
5- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid (1) 4- ( 2- (Benzoyloxymethyl) thiazol-4-yl) benzoic acid

To a solution of 4- (bromoacetyl) benzoic acid (10 g, 41.14 mmol) in N, N-dimethylformamide (40 ml) was added 2- (benzoyloxy) ethanethioamide (8.03 g, 41.14 mmol) under ice cooling. And stirred at room temperature for 1.5 hours. After completion of the reaction, sodium hydrogen carbonate (3.46 g, 41.14 mmol) and water were added under ice cooling, and the mixture was stirred at room temperature for 0.5 hour, and then the precipitate was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (13.089 g, 93.3%).
(2) (4- (4-hydroxymethylphenyl) thiazol-2-yl) methyl benzoate

To a suspension of 4- (2- (benzoyloxymethyl) thiazol-4-yl) benzoic acid (0.5 g, 1.47 mmol) obtained in Example 1-1 (1) in tetrahydrofuran (5 ml) at room temperature. Lower 1,1′-carbonyldiimidazole (0.358 g, 2.21 mmol) was added and stirred at 65 ° C. for 2 hours. Subsequently, an aqueous solution of sodium borohydride (0.056 g, 1.47 mmol) was added dropwise at room temperature, and the mixture was stirred at the same temperature for 20 minutes. After completion of the reaction, extraction was performed by adding ethyl acetate and aqueous sodium hydrogen carbonate solution, and the organic layer was washed with water and saturated brine, and then dried over sodium sulfate. After the solvent was distilled off, the residue was washed with a hexane-ethyl acetate mixed solvent and collected by filtration. The obtained solid was dried under reduced pressure to give the title compound (370.7 mg, 77.5%
)
(3) (4- (4-Chloromethylphenyl) thiazol-2-yl) methyl benzoate

To a solution of (4- (4-hydroxymethylphenyl) thiazol-2-yl) methyl benzoate (5.55 g, 17.06 mmol) obtained in Example 1-1 (2) in chloroform (100 ml) was cooled with ice. Thionyl chloride (1.49 ml, 20.67 mmol) and N, N-dimethylformamide (catalytic amount) were added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, chloroform was added to the residue obtained by distilling the solvent, and the mixture was concentrated. Hexane was added and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (5.804 g, 98.9%).
(4) (4- (4- (N-isopropyl-4- (1-ethylpropyl) phenylamino) methylphenyl) thiazol-2-yl) methanol

A solution of N-isopropyl-4- (1-ethylpropyl) aniline (7.34 g, 35.78 mmol) in N, N-dimethylacetamide (35 ml) was obtained in Example 1-1 (3) (4- (4-Chloromethylphenyl) thiazol-2-yl) methyl benzoate (11.18 g, 32.52 mmol), potassium carbonate (4.95 g, 35.78 mmol), potassium iodide (0.54 g, 3.25 mmol). Sequentially added and stirred at 80 ° C. for 3 hours, potassium carbonate (0.449 g, 3.252 mmol) was added and stirred at 70 ° C. for 12 hours. After completion of the reaction, 50% ethyl acetate-hexane mixed solution and water were added for extraction, and the organic layer was washed successively with water and saturated brine, and then dried over sodium sulfate. To the residue obtained by distilling off the solvent, tetrahydrofuran (60 ml), methanol (60 ml) and 1N aqueous sodium hydroxide solution (48.8 ml) were successively added at room temperature, followed by stirring at 75 ° C. for 1.5 hours. . After completion of the reaction, the solvent was distilled off, extraction was carried out by adding ethyl acetate and water, washed successively with water and saturated brine, and the organic layer was dried over sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to obtain the title compound (10.664 g, 80.3%).
(5) (4- (4- (N-isopropyl-4- (1-ethylpropyl) phenylamino) methylphenyl) thiazol-2-yl) methyl chloride hydrochloride

After adding thionyl chloride (2.7 ml, 37.1 mmol) and N, N-dimethylformamide (catalytic amount) to chloroform (30 ml) at room temperature, it was obtained in Example 1-1 (4) (4- ( A solution of 4- (N-isopropyl-4- (1-ethylpropyl) phenylamino) methylphenyl) thiazol-2-yl) methanol (10.1 g, 24.7 mmol) in chloroform (30 ml) was added dropwise under ice cooling. Stir at room temperature for 1 hour. After completion of the reaction, chloroform was added to the residue obtained by evaporating the solvent, and the mixture was concentrated. Ethyl acetate was added and the mixture was stirred for 0.5 hour. The precipitate was collected by filtration, and the obtained solid was dried under reduced pressure to give the title compound (10.23 g, 89.4%).
(6) 5- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid methyl ester

(4- (4- (N-isopropyl-4- (1-ethylpropyl) phenylamino) methylphenyl) thiazol-2-yl) methyl chloride hydrochloride obtained in Example 1-1 (5) (9. 92 g, 21.4 mmol), N-N-dimethylformamide solution of methyl 5-hydroxynicotinate (3.61 g, 23.5 mmol), potassium carbonate (6.8 g, 49.2 mmol), potassium iodide under ice-cooling (0.355 g, 2.14 mmol) was added, and the mixture was stirred at 60 ° C. for 12 hours. After completion of the reaction, ethyl acetate and water were added for extraction, and the organic layer was washed successively with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) followed by (chloroform: ethyl acetate = 20: 1) to give the title compound (5.32 g, 45 0.7%).
(7) 5- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazol-2-ylmethoxy} -nicotinic acid

5- {4- [4-({[4- (1-Ethyl-propyl) -phenyl] -isopropyl-amino} -methyl) -phenyl] -thiazole-2 obtained in Example 1-1 (6) To a 50% tetrahydrofuran-methanol (32 ml) solution of -ylmethoxy} -nicotinic acid methyl ester (5.32 g, 9.78 mmol), 2N aqueous sodium hydroxide solution (9.78 ml) was added at room temperature, and the mixture was heated at 75 ° C. for 2 hours. Stir. After completion of the reaction, 2N hydrochloric acid (9.78 ml) was added under ice cooling, and the precipitate was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (5.00 g, 96.5%).
1H NMR (DMSO-d6, 300 MHz) δ 0.69 (t, J = 7.3 Hz, 6 H), 1.16 (d, J = 6.5 Hz, 6 H), 1.48- 1.31 (m, 2 H), 1.64- 1.48 (m, 2 H), 2.19- 2.06 (m, 1 H), 4.23 (quint, J
= 6.6 Hz, 1 H), 5.67 (s, 2 H), 6.62 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 7.36 (d, J = 8.2 Hz , 2 H), 7.90 (d, J = 8.2 Hz, 2 H), 7.99 (dd, J = 3.0, 1.5 Hz, 1 H), 8.11 (s, 1 H), 8.64 (d, J = 2.9 Hz, 1 H), 8.72 (d, J = 1.5 Hz, 1 H), 13.43 (br s, 1 H)
Melting point 201.5 ° C
Examples 1-2 to 1-186
The compounds of Examples 1-2 to 1-186 were produced by the same method as in Example 1-1 and using other conventional methods as necessary. The structural formula and physical property values of the obtained compound are shown in the following table together with Example 1-1.

Example 2-1
{Benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) benzyl] amino} -phenyl) -oxazol-2-ylmethyl] -amino} -acetic acid (1) 4- (1-propyl Butyl) benzaldehyde

To a chloroform (50 ml) solution of titanium tetrachloride (18.7 ml, 170 mmol), (1-propylbutyl) benzene (10.0 g, 56.7 mmol) and dichloromethyl methyl ether (7.70 ml, 85.85 ml) were added under ice cooling. 1 mmol) chloroform (40 ml)
The solution was added dropwise and stirred at the same temperature for 1 hour. The reaction mixture was poured into ice (100 g) and stirred at room temperature for 1 hour. The organic layer was washed successively with water, 0.5N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. After filtration and removal of the solvent, the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane 1:50) to obtain the title compound (10.0 g, yield 87%).
(2) N-methyl-4- (1-propylbutyl) benzylamine hydrochloride

To an ethanol solution of 4- (1-propylbutyl) benzaldehyde (1.00 g, 4.89 mmol) obtained in Example 2-1 (1), a methanol solution of methylamine (2 mol / l, 2) was cooled with ice. .94 ml) was added and stirred at room temperature for 30 minutes. After removing the solvent, the residue was dissolved in tetrahydrofuran (10 ml), sodium borohydride (285 mg, 7.53 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ethanol was added and the mixture was stirred for 6 hours. The solvent was removed, chloroform (10 ml) was added, water and 2N-hydrochloric acid were added under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the organic layer, a saturated aqueous sodium hydrogen carbonate solution and di-tert-butyl dicarbonate (1.28 g, 5.87 mmol) were added and stirred for 3 hours. The organic layer was washed with saturated brine and dried over sodium sulfate. After removing the solvent, the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane 5:95) to obtain an oily substance.
The obtained oil was dissolved in ethyl acetate (2 ml), 4N-hydrogen chloride ethyl acetate solution (10 ml) was added, and the mixture was stirred for 3 hr. Hexane (10 ml) was added, and the precipitate was collected by filtration and dried to give the title compound (650 mg, yield 52%).
(3) (4- (4-Bromophenyl) oxazol-2-yl) methanol

Under an argon atmosphere, a solution of 2,2,6,6-tetramethylpiperidine (227 mg, 1.61 mol) in tetrahydrofuran (3.0 ml, 13 v / w) was added at 0 ° C. with n-butyllithium (1.56 M hexane solution). , 0.944 ml, 1.47 mmol), and stirred for 30 minutes. After cooling to -78 ° C., 4- (4-bromophenyl) oxazole (300 mg, 1.34 mmol) was added and stirred for 45 minutes. A suspension of paraformaldehyde (100 mg, 3.35 mmol) in tetrahydrofuran (1.5 ml, 15 v / w) was added and stirred for 20 minutes. After raising the temperature to room temperature, a saturated aqueous ammonium chloride solution (5.0 ml) was added. After removing the solvent, the mixture was extracted with ethyl acetate (15 ml), washed with saturated brine (10 ml), and dried over sodium sulfate (1.0 g). After removing the solvent, the residue was purified by silica gel column chromatography (developing solvent: chloroform to chloroform: ethyl acetate = 8: 2) to obtain the title compound (210 mg, yield 62%).
(4) N-benzyl-N-((4- (4-bromophenyl) oxazol-2-yl) methyl) glycine ethyl ester

Under an argon atmosphere, chloroform (4.0 ml, 20 v / w) of (4- (4-bromophenyl) oxazol-2-yl) methanol (200 mg, 0.787 mmol) obtained in Example 2-1 (3) To the suspension was added thionyl chloride (103 mg, 0.866 mmol) at 0 ° C. After stirring at room temperature for 1 hour, the mixture was stirred at 60 ° C. for 1 hour. At room temperature, thionyl chloride (103 mg, 0.866 mmol) was added and stirred for 12 hours. After removing the solvent, acetonitrile (2.0 ml), N-benzylglycine ethyl ester (0.221 ml, 1.18 mmol), potassium carbonate (326 mg, 2.36 mmol), and potassium iodide (13 mg, 0.0787 mmol) were sequentially added. It was. Stir at 60 ° C. for 1 hour. Distilled water (5.0 ml) was added at room temperature, extracted with a mixed solvent of hexane: ethyl acetate = 1: 1, washed with saturated brine (5.0 ml), and dried over sodium sulfate (1.0 g). did. After removing the solvent, the residue was purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 9: 1) to obtain the title compound (220 mg, yield 65%).
(5) {Benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) benzyl] amino} -phenyl) -oxazol-2-ylmethyl] -amino} -acetic acid ethyl ester

N-benzyl-N-((4- (4-bromophenyl) oxazol-2-yl) methyl) glycine ethyl ester (200 mg, 0.466 mmol) obtained in Example 2-1 (4) under argon atmosphere To a dioxane (2.0 ml) solution of N-methyl-4- (1-propylbutyl) benzylamine hydrochloride (131 mg, 0.512 mmol) obtained in Example 2-1 (2), (R) -(+)-2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (29.0 mg, 0.0466 mmol), cesium carbonate (334 mg, 1.03 mmol), palladium acetate (5.20 mg, 0.0233 mmol) was added sequentially. After stirring at 90 ° C. for 18 hours, (R)-(+)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (70.0 mg, 0.112 mmol), palladium acetate ( 10.0 mg, 0.0445 mmol) was added. After stirring at 100 ° C. for 3 hours, cesium carbonate (200 mg, 0.614 mmol) was added and stirred for 12 hours. 4-Morpholinoaniline (83.0 mg, 0.466 mmol) was added, and the mixture was stirred for 4 hours and filtered through Celite at room temperature. After removing the solvent, the residue was purified by silica gel column chromatography (developing solvent hexane: ethyl acetate = 9: 1) to obtain the title compound (35.0 mg, yield 13%).
(6) {benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) benzyl] amino} -phenyl) -oxazol-2-ylmethyl] -amino} -acetic acid

{Benzyl- [4- (4- {methyl- [4- (1-propyl-butyl) benzyl] amino} -phenyl) -oxazole-2-y] obtained in Example 2-1 (5) under an argon atmosphere. To a solution of ylmethyl] -amino} -acetic acid ethyl ester (30.0 mg, 0.0528 mmol) in tetrahydrofuran (0.50 ml), methanol (0.50 ml), 2N aqueous sodium hydroxide solution (0.0528 ml, 0.106 mmol) were added. added. After stirring at 70 ° C. for 1.5 hours, 1N hydrochloric acid (0.106 ml, 0.106 mmol) and distilled water (2.0 ml) were sequentially added at room temperature. After removing the solvent, hexane (0.2 ml) and distilled water (2.0 ml) were sequentially added. The precipitate was collected by filtration and dried to give the title compound (16.0 mg, yield 56%).
1HNMR (DMSO-d6,300MHz) δ0.79 (t, J = 7.3 Hz, 6 H), 0.95- 1.20 (m, 4 H), 1.40-1.65 (m, 4 H), 2.40-2.60 (m, 1 H), 3.02 (s, 3 H), 3.81 (s, 2 H), 3.93 (s, 2 H), 4.57 (s, 2 H), 6.78 (d, J = 8.8 Hz, 2 H), 7.00- 7.40 (m, 9 H), 7.55 (d, J = 8.8 Hz, 2 H), 8.30 (s, 1 H), 12.30 (br s, 1 H).
Melting point 129 ° C-131 ° C
The structural formula and physical property values of Example 2-1 are shown in the following table.

Example 3-1.
5- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid (1) (4- (4-hydroxyphenyl) thiazole-2 -Yl) methyl benzoate

To a solution of 2- (benzoyloxy) ethanethioamide (4 g, 20.488 mmol) and sodium bicarbonate (1.72 g, 20.488 mmol) in N, N-dimethylacetamide (4 ml) at room temperature, 2-bromo-4′- A solution of hydroxyacetophenone (5 g, purity 88%, 20.488 mmol) in N, N-dimethylacetamide (8 ml) was added dropwise and stirred at the same temperature for 2 hours. After completion of the reaction, ethanol and water were added, and the precipitate was collected by filtration and washed with 50% ethanol. The obtained solid was dried under reduced pressure to obtain the title compound (5.336 g, 84.1%).
(2) (4- (4- (4- (1-propylbutyl) benzyloxy) phenyl) thiazol-2-yl) methyl benzoate

To a solution of (4- (4-hydroxyphenyl) thiazol-2-yl) methyl benzoate (14.0 g, 44.9 mmol) obtained in Example 3-1 (1) in N, N-dimethylacetamide (70 ml). 4- (1-propylbutyl) benzyl chloride (10.1 g, 44.9 mmol), potassium carbonate (12.4 g, 89.9 mmol), and potassium iodide (75 mg, 0.45 mmol) were added. Stir for hours. After allowing to cool, ethyl acetate was added, washed successively with water and saturated brine, and dried over magnesium sulfate. After filtration and removal of the solvent, ethanol (120 ml) was added and heated to 50 ° C. After allowing to cool, the precipitated crystals were collected by filtration and dried to give the title compound (19.5 g, yield 87%).
(3) (4- (4- (4- (1-propylbutyl) benzyloxy) phenyl) thiazol-2-yl) methanol

To (4- (4- (4- (1-propylbutyl) benzyloxy) phenyl) thiazol-2-yl) methyl benzoate (26.5 g, 53.1 mmol) obtained in Example 3-1 (2) Methanol (159 ml), tetrahydrofuran (27 ml), and 2N aqueous sodium hydroxide solution (39.8 ml, 79.6 mmol) were added, and the mixture was stirred at 80 ° C. for 1 hour. After removing the solvent, water (265 ml) was added and stirred at room temperature for 1 hour. The crystals were collected by filtration, dissolved in toluene (100 ml) and ethyl acetate (10 ml), and washed with saturated brine. The extract was dried over magnesium sulfate, filtered and removed to give the title compound (20.5 g, yield 98%).
(4) (4- (4- (4- (1-propylbutyl) benzyloxy) phenyl) thiazol-2-yl) methyl chloride

Chloroform of (4- (4- (4- (1-propylbutyl) benzyloxy) phenyl) thiazol-2-yl) methanol (20.5 g, 51.8 mmol) obtained in Example 3-1 (3) (103 ml) To the solution was added thionyl chloride (9.17 g, 77.7 mmol), and the mixture was stirred at room temperature for 1 hour. After removing the solvent, the title compound (21.9 g, quantitative) was obtained.
(5) 5- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid methyl ester

To (4- (4- (4- (1-propylbutyl) benzyloxy) phenyl) thiazol-2-yl) methyl chloride (13.0 g, 31.4 mmol) obtained in Example 3-1 (4) N, N-dimethylacetamide (104 ml), methyl 5-hydroxynicotinate (5.25 g, 40.8 mmol), potassium carbonate (13.0 g, 94.2 mmol), potassium iodide (520 mg, 3.1 mmol) were added. And stirred at 75 ° C. for 2 hours. After allowing to cool, ethyl acetate was added, and the mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. After drying over magnesium sulfate, filtration and removal of the solvent, the residue was purified by silica gel column chromatography (eluent: toluene-ethyl acetate 5: 1). The obtained crude crystals were slurry washed with ether to obtain the title compound (9.91 g, yield 59%).
(6) 5- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid

5- (4- {4- [4- (1-propyl-butyl) -benzyloxy] -phenyl} -thiazol-2-ylmethoxy) -nicotinic acid methyl ester obtained in Example 3-1 (5) To tetrahydrofuran (62.5 ml), ethanol (62.5 ml), and 2N aqueous sodium hydroxide solution (17.9 ml, 35.8 mmol) were added to 9.50 g (17.9 mmol), and the mixture was stirred at 70 ° C. for 2 hours 30 minutes. . Under ice-cooling, 2N-hydrochloric acid (17.9 ml, 35.8 mmol) was added, and the mixture was concentrated under reduced pressure. Ethanol (19 ml) and water (9.5 ml) were added, and after stirring, the crystals were collected by filtration and dried to give the title compound (9.15 g, yield 99%). 1HNMR (DMSO-d6,400MHz) δ0.81 (t, J = 7.3Hz, 6H), 1.05-1.13 (m, 4H), 1.48-1.57 (m, 4H),
2.5-2.56 (m, 1H), 5.09 (s, 2H), 5.66 (s, 2H), 7.09 (d, J = 9.04Hz, 2H), 7.19 (d, J = 8.32Hz 2H), 7.38 (d, J = 8.12Hz, 2H), 7.91 (d, J = 9.04Hz, 2H), 7.98-7.99 (m, 1H), 8.03 (s, 1H), 8.64 (d, J = 3Hz, 1H), 8.72 (d , J = 1.4Hz, 1H), 13.52 (s, 1H)
Melting point 172-174 ° C
Examples 3-2 to 3-132
The compounds of Examples 3-2 to 3-132 were produced by the same method as in Example 3-1, and if necessary, using other conventional methods. The structural formula and physical property values of the obtained compound are shown in the following table together with Example 3-1.

Example 4-1
[(1-Methyl-1H-benzimidazol-2-ylmethyl) -5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl] -amino] -acetic acid (1) N- (1-methyl-1H-benzimidazol-2-ylmethyl) glycine ethyl ester / hydrochloride

To a suspension of 2-chloromethyl-1-methyl-1H-benzimidazole hydrochloride (81.135 g, 0.374 mmol) in acetonitrile (800 ml) was added glycine ethyl ester hydrochloride (156.5 g, 1.12 mol), carbonic acid. Potassium (284.1 g, 2.06 mol) and potassium iodide (6.2 g, 0.037 mol) were added, and the mixture was stirred at 75 ° C. for 1.5 hours. After completion of the reaction, extraction was performed by adding ethyl acetate and water, and the organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off, the resulting residue was dissolved in ethyl acetate, 4N hydrochloric acid / ethyl acetate solution (93 ml) was added, and the solvent was distilled off. Ethyl acetate was added to the obtained residue, and the resulting solid was collected by filtration to give the title compound (74.4 g, 70%).
(2) 5- (4-hydroxymethylphenyl) thiophene-2-carbaldehyde

5-bromothiophene-2-carbaldehyde (125.7 g, 0.658 mol), 4-hydroxymethylphenylboronic acid (100 g, 0.658 mol), potassium carbonate (136.43 g, 0.987 mol) in 50% methanol ( 880 ml) suspension was added bis (triphenylphosphine) palladium (II) dichloride (4.62 g, 6.58 mmol) and stirred at 80 ° C. for 1.5 hours. After completion of the reaction, the resulting solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (137.2 g, 96%).
(3) 5- (4-Chloromethylphenyl) thiophene-2-carbaldehyde

To an acetonitrile solution of 5- (4-hydroxymethylphenyl) thiophene-2-carbaldehyde (20 g, 91.6 mmol) and triethylamine (15.3 ml, 110 mmol) obtained in Example 4-1 (2), ice-cooled. Lower methanesulfonyl chloride (8.51 ml, 110 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Lithium chloride (7.77 g, 183.3 mmol) was added to the reaction mixture, and the mixture was stirred at 55 ° C. for 1 hr. After completion of the reaction, water was added at room temperature, and the resulting solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (19.3 g, 89%).
(4) 5- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophene-2-carbaldehyde

4- (1-propylbutyl) phenol (15.6 g, 81.1 mmol) in N, N-
In a dimethylacetamide (192 ml) solution, 5- (4-chloromethylphenyl) thiophene-2-carbaldehyde obtained in Example 4-1 (3) (19.2 g, 81.1 mmol), potassium carbonate (22.4 g) 162.2 mmol) and potassium iodide (2.69 g, 16.2 mmol) were sequentially added, and the mixture was stirred at 90 ° C. for 1.5 hours. After completion of the reaction, extraction was performed by adding ethyl acetate and water at room temperature, and the organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. The residue obtained by distilling off the solvent was stirred with hexane / diisopropyl ether = 3/1, and the resulting solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (25.9 g, 81%).
(5) (5- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophen-2-yl) methanol

5- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophene-2-carbaldehyde (25.9 g, 66 mmol) of tetrahydrofuran (260 ml) obtained in Example 4-1 (4) and Sodium borohydride (2.5 g, 66 mmol) was added to an ethanol (260 ml) solution under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. After completion of the reaction, ethyl acetate, saturated aqueous sodium hydrogencarbonate and water were added to the residue obtained by partially concentrating the solvent, and the mixture was stirred for 0.5 hours and extracted. The organic layer was washed with saturated brine, and then magnesium sulfate. And dried. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 → 10: 1) to obtain the title compound (23.6 g, 91%).
(6) (5- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophen-2-yl) methyl chloride

Chloroform of (5- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophen-2-yl) methanol (23.6 g, 59.8 mmol) obtained in Example 4-1 (5). (354 ml) To the solution was added thionyl chloride (8.73 ml, 119.6 mmol) at room temperature, and the mixture was stirred at the same temperature for 1 hour. After completion of the reaction, the solvent was distilled off and chloroform was added to the resulting residue to concentrate, followed by drying under reduced pressure to obtain the title compound (24.6 g, 100%).
(7) [(1-Methyl-1H-benzimidazol-2-ylmethyl) -5- {4- [4
-(1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl] -amino] -acetic acid ethyl ester

(5- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophen-2-yl) methyl chloride (0.687 g, 1.66 mmol) obtained in Example 4-1 (6) To an acetonitrile solution, N- (1-methyl-1H-benzimidazol-2-ylmethyl) glycine ethyl ester / hydrochloride (0.674 g, 1.83 mmol) obtained in Example 4-1 (1), potassium carbonate (0.69 g, 5.0 mmol) and potassium iodide (0.055 g, 0.33 mmol) were added, and the mixture was stirred at 80 ° C. for 1.5 hours. After completion of the reaction, extraction was performed by adding ethyl acetate and water, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 → 20: 1) to obtain the title compound (0.633 g, 61%).
(8) [(1-Methyl-1H-benzimidazol-2-ylmethyl) -5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl] -amino ] -Acetic acid

[(1-Methyl-1H-benzimidazol-2-ylmethyl) -5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} obtained in Example 4-1 (7) To a 50% tetrahydrofuran-ethanol (100 ml) solution of -thiophen-2-ylmethyl] -amino] -acetic acid ethyl ester (5 g, 8.01 mmol), 1N aqueous sodium hydroxide solution (16 ml) was added at room temperature. Stir for 1 hour. After completion of the reaction, 1N-hydrochloric acid (16 ml) was added under ice cooling, and the resulting solid was stirred at room temperature and collected by filtration. The obtained solid was dried under reduced pressure to obtain the title compound (4.63 g, 97%).
1H NMR (DMSO-d6, 300 MHz) δ 0.79 (t, J = 7.3 Hz, 6 H), 0.96- 1.18 (m, 4 H), 1.34- 1.60 (m, 4 H), 3.36 (s, 2 H ), 3.88 (s, 3 H), 4.04 (s, 2 H), 4.16 (s, 2 H), 5.06 (s, 2 H), 6.92 (d, J = 8.7 Hz, 2 H), 7.01 (d , J = 3.4 Hz, 1 H), 7.07 (d, J =
8.7 Hz, 2 H), 7.14- 7.26 (m, 2 H), 7.35 (d, J = 3.4 Hz, 1 H), 7.46 (d, J = 8.3 Hz, 2 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.58-7.65 (m, 3 H), 12.52 (br s, 1 H)
Example 4-40
[(1-Methyl-1H-benzimidazol-2-ylmethyl) -5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethyl] -amino] -acetic acid p-Toluenesulfonate

[(1-Methyl-1H-benzimidazol-2-ylmethyl) -5- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophene- obtained in Example 4-1 To a suspension of 2-ylmethyl] -amino] -acetic acid (200 mg, 0.336 mmol) in 2-butanone (5 ml) was added p-toluenesulfonic acid monohydrate (64 mg, 0.37 mmol) and room temperature for 30 minutes. Stir. The crystals were collected by filtration and dried to give the title compound (231 mg, 90%).
1H NMR (DMSO-d6, 300 MHz) δ0.79 (t, J = 7.3Hz, 6H), 0.95-1.20 (m, 4H), 1.32-1.60 (m,
4H), 2.28 (s, 3H), 2.40-2.54 (m, 1H), 3.62 (s, 2H), 4.00 (s, 3H), 4.19 (s, 2H), 4.46 (s, 2H), 5.05 (s , 2H), 6.92 (d, J = 8.6Hz, 2H), 6.98-7.14 (m, 5H), 7.25 (d, J = 3.6Hz, 1H), 7.36-7.58 (m, 8H), 7.76 (d, J = 9.0Hz, 1H), 7.89 (d, J = 9.0Hz, 1H)
Melting point 100 ° C-135 ° C
Example 4-2
5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid (1) 4- (4-hydroxymethylphenyl) thiophene-2 -Carval Dehydr

To a solution of 4-bromothiophene-2-carbaldehyde (100 g, 0.523 mol) in tetrahydrofuran (500 ml) was added bis (triphenylphosphine) palladium (II) dichloride (3.67 g, 52.3 mmol), 4-hydroxymethylphenyl. Boronic acid (79.5 g, 0.523 mol), sodium hydrogen carbonate (66.0 g, 0.786 mol) and water (1000 ml) were added, and the mixture was stirred at an internal temperature of 62 to 63 ° C. for 3 hours. After allowing to cool, ethyl acetate was added to the reaction solution, and the organic layer was washed with saturated brine and concentrated to obtain 140 g of a crude product. Toluene (400 ml) and hexane (100 ml) were added to the resulting crude product and stirred.
The solid was collected by filtration and dried to give the title compound (95.4 g, 83%).
(2) 4- (4-Chloromethylphenyl) thiophene-2-carbaldehyde

To a solution of 4- (4-hydroxymethylphenyl) thiophene-2-carbaldehyde (95.4 g, 0.437 mol), triethylamine (73.1 ml, 0.524 mol) in N, N-dimethylformamide (763 ml) Lower methanesulfonyl chloride (40.6 ml, 0.524 mol) was added dropwise and stirred at room temperature for 2 hours. Lithium chloride (37.1 g, 0.874 mol) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 1 hr. After allowing to cool, water was added and the resulting solid was collected by filtration. The obtained solid was suspended in diisopropyl ether (465 ml) and stirred at an internal temperature of 60 to 65 ° C. for 1.5 hours. After allowing to cool, the solid was collected by filtration and dried to give the title compound (83.2 g, 80%).
(3) (4- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophen-2-yl) methanol

To a solution of 4- (4-chloromethylphenyl) thiophene-2-carbaldehyde (21.1 g, 88.9 mmol) in N, N-dimethylacetamide (105 ml) 4- (1-propylbutyl) phenol (18.7 g, 97.8 mmol), potassium carbonate (36.8 g, 267 mmol), and potassium iodide (1.47 g, 8.89 mmol) were sequentially added, and the mixture was stirred at 90 ° C. for 1.5 hours. After completion of the reaction, extraction was performed by adding ethyl acetate and water at room temperature, and the organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. The residue (68 g) obtained by evaporating the solvent was dissolved in ethanol (100 ml), sodium borohydride (37.8 g, 88.9 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. Water and ethyl acetate were added to the reaction solution, and the organic layer was washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: methanol = 100: 1 → 50: 1) to obtain a crude product (29.9 g). The crude product (14.5 g) was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5 → 1: 4) to obtain the title compound (11.9 g).
(4) (4- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophen-2-yl) methyl chloride

To a solution of (4- (4- (4- (1-propyl-butyl) phenoxymethyl) -phenyl) -thiophen-2-yl) methanol (11.9 g, 30.2 mmol) in chloroform (60 ml) was added thionyl chloride ( 4.40 ml, 60.4 mmol) was added and stirred for 30 minutes at room temperature. The solvent was distilled off, thionyl chloride (10.0 ml, 137 mmol) was added, and the mixture was stirred for 20 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and chloroform was added to the resulting residue and concentrated to obtain the title compound (12.5 g, 100%).
(5) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid methyl ester

(4- (4- (4- (1-propylbutyl) phenoxymethyl) phenyl) thiophen-2-yl) methyl chloride (5.00 g, 12.1 mmol) to N, N-dimethylacetamide (25 ml), 5- Hydroxynicotinic acid methyl ester (2.04 g, 13.3 mmol), cesium carbonate (11.8 g, 36.3 mmol), potassium iodide (201 mg, 1.21 mmol), tetra-n-butylammonium bromide (390 mg, 1. 21 mmol) was added and the mixture was stirred at 60 ° C. for 1.5 hours. After allowing to cool, ethyl acetate was added, and the mixture was washed successively with water and saturated brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 5 → 1: 2) to obtain the title compound (5.19 g, 81%).
(6) 5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid

5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid methyl ester (5.04 g, 9.52 mmol) in tetrahydrofuran (25 ml) ), Ethanol (25 ml), 2N aqueous sodium hydroxide solution (5.00 ml, 10 mmol) were added, and the mixture was stirred at 60 ° C. for 1.5 hours. After allowing to cool, 2N-hydrochloric acid (5.00 ml, 10 mmol) and water (30 ml) were added, and the precipitated solid was collected by filtration and dried to give the title compound (4.77 g, yield 97%).
1H NMR (DMSO-d6, 300 MHz) δ 0.80 (t, J = 7.3Hz, 6H), 1.00-1.12 (m, 4H), 1.38-1.57 (m, 4H), 2.40-2.50 (m, 1H), 5.07 (s, 2H), 5.48 (s, 2H), 6.93 (d, J = 8.6Hz, 2H), 7.07 (d,
J = 8.6Hz, 2H), 7.49 (d, J = 7.9Hz, 2H), 7.70-7.70 (m, 1H), 7.72 (d, J = 8.3Hz, 2H), 7.88-7.89 (m, 1H), 7.91 (d, J = 1.5Hz, 1H), 8.56 (d, J = 2.6Hz, 1H), 8.69 (d, J = 1.5Hz, 1H),
13.41 (brs, 1H)
Melting point 157-159 ° C
Example 4-41
5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid sulfate

5- (4- {4- [4- (1-propyl-butyl) -phenoxymethyl] -phenyl} -thiophen-2-ylmethoxy) -nicotinic acid (200 mg, 0.388 mmol) obtained in Example 4-2. Concentrated sulfuric acid (0.0207 ml, 0.388 mmol) was added to a suspension of 2-butanone (2 ml) in 1) at room temperature. The solid was collected by filtration and dried to give the title compound (224 mg, 94% yield).
1H NMR (DMSO-d6, 300 MHz) 0.80 (t, J = 7.3Hz, 6H), 0.98-1.15 (m, 4H), 1.38-1.59 (m, 4H), 2.39-2.54 (m, 1H), 5.07 (s, 2H), 5.52 (s, 2H), 6.93 (d, J = 8.6Hz, 2H), 7.07 (d, J = 8.7Hz, 2H), 7.49 (d, J = 8.3Hz, 2H), 7.71 (s, 1H), 7.72 (d, J = 6.4Hz, 2H), 7.93 (d, J = 1.5Hz, 1H), 8.00 (brs, 1H), 8.65-8.67 (m, 1H), 8.73-8.76 ( m, 1H)
Melting point 125 ° C (decomposition)
Examples 4-3 to 4-39 and 4-42 to 4-107
In the same manner as in Example 4-1, 4-2, 4-40 or 4-41, and using other conventional methods as necessary, Examples 4-3 to 4-39 and Examples 4-42 to 4-107 was prepared. The structural formulas and physical property values of the obtained compounds are shown in the following table together with Examples 4-1, 4-2, 4-40 and 4-41.

Formulation examples are given below, but the present invention is not limited thereto.
Formulation Example (a) 10 g of the compound of Example 1
(B) Lactose 50g
(C) Corn starch 15g
(D) Sodium carboxymethyl cellulose 44 g
(E) Magnesium stearate 1g
The whole amount of (a), (b), (c) and 30 g of (d) are kneaded with water, and after vacuum drying, granulation is performed. This granulated powder is mixed with 14 g of (d) and 1 g of (e), and tableted with a tableting machine to produce 1000 tablets containing 10 mg of (a) per tablet.

Next, the results of tests conducted on the protein tyrosine phosphatase 1B inhibitory action of the present invention are shown.
(Test example)
Test Example 1 (Protein tyrosine phosphatase 1B inhibitory action)
-Preparation of assay buffer:
50 mM Tris-HCl buffer (pH 7.5), 50 mM NaCl and 3 mM dithiothreitol (DTT) were prepared.
・ Sample preparation:
10 mM DMSO solutions of 0.1, 0.3, 1, 3 and 10 μM of the test compound were diluted with the above assay buffer so that the final dimethyl sulfoxide (DMSO) concentration was 1% or less. As a control, an assay buffer was used.
-Preparation of substrate:
A synthetic peptide obtained by phosphorylating three tyrosines at 12 amino acids of the insulin receptor sequence 1142 to 1153 was diluted with the above assay buffer to prepare 80 μM.
・ Enzyme preparation:
Recombinant human protein tyrosine phosphatase 1B manufactured by UBI was diluted with the above assay buffer (1.2 ng / 25 μl).

(Evaluation methods)
To the 96-well plate, 10 μl of the sample prepared as described above and 25 μl of the substrate were sequentially added, and 25 μl of the enzyme prepared as described above was added and mixed. After incubation at room temperature for 60 minutes, 120 μl of malachite green (Biomol), which is a phosphorus color former, was added, and further incubated at room temperature for 20 minutes for color development. The absorbance at 650 nm was measured with a plate reader to evaluate the protein tyrosine phosphatase 1B inhibitory action of the test compound. The results are shown in Tables 5-6.

Examples 1-1, 1-27, 1-48, 1-65, 1-66, 1-68, 1-71, 1-77, 1-78, 1-80, 1-86, 1- 88, 1-89, 1-94, 1-97, 1-105, 1-109, 1-110, 1-111, 1-119, 1-120, 1-126, 1-130, 1-132, 1-138, 1-139, 1-140, 1-141, 1-146, 1-149, 1-153, 1-155, 1-156, 1-160, 1-161, 1-162, 3- 1, 3-117, 3-120, 3-124, 4-1, 4-2, 4-6, 4-8, 4-9, 4-17, 4-18, 4-19, 4-21, Targeting compounds 4-27, 4-30, 4-31, 4-34, 4-36 and 4-37, T cell protein tyrosine phosphors of these test compounds Evaluated over peptidase inhibitory action, a result of comparison with the protein tyrosine phosphatase 1B inhibitory activity of the described, IC ₅₀ for protein tyrosine phosphatase 1B was a low of 1/60 or less than the IC ₅₀ for T cell protein tyrosine phosphatase .

Test Example 2 (blood glucose lowering effect)
A 0.5% methylcellulose suspension of the test compound was orally administered to 6 to 9-week-old male ob / ob mice grouped according to blood glucose level at satiation. In addition, only 0.5% methylcellulose solution was administered to the control group.
Blood collection was performed under fasting conditions. That is, the fasting condition was started by removing food simultaneously with the administration of the test compound, and blood was collected from the orbital vein under anesthesia 3 hours after administration. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose measurement kit). In the evaluation, the rate of decrease in blood glucose level in the test compound administration group relative to the control group was shown in%. The results are shown in Tables 5 to 9.

Test Example 3 (Effect of combined use with insulin on blood glucose lowering effect)
7-week-old male SD rat, 0.5% methylcellulose suspension of test compound {Note: Example 3-40 (30 mg / kg)} once a day for 8 days (combined test compound and insulin) Group) or 0.5% methylcellulose solution alone (insulin administration group) was orally administered, and 3 hours later, 0.6 U / kg of insulin was administered subcutaneously.
Blood was collected from the tail vein on the first day of administration, before administration of insulin on the 8th day, and 1 hour after that. The blood sample was fasted after insulin administration. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose measurement kit). In the evaluation, the decrease rate of the blood glucose level after 1 hour with respect to the test compound and the combination of insulin and each group administered with insulin before the insulin administration was expressed in%. The results are shown in Table 10.

Test Example 4 (Effect of combined use with glibenclamide on blood glucose lowering effect)
10-week-old female ob / ob mice grouped according to satiety blood glucose level were mixed with 0.5% methylcellulose suspension of test compound {Appendix: Example 4-2 (1 mg / kg)} (test compound administration group), glibenclamide 3 mg. / Kg of 0.5% methylcellulose suspension (glibenclamide administration group), 0.5% methylcellulose suspension of test compound and 0.5 mg methylcellulose suspension of glibenclamide 3 mg / kg simultaneously (test compound and glibenclamide combination group) or 0.5 Only% methylcellulose solution (control group) was orally administered.

  Blood collection was performed under fasting conditions. That is, the fasting condition was started by removing food simultaneously with the administration of the test compound, and blood was collected from the orbital vein under anesthesia 3 and 5 hours after administration. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose kit). In the evaluation, the rate of decrease in blood glucose level in each of the other groups relative to the control group was shown in%. The results are shown in Table 11.

Test Example 5 (Effect of combined use with tolbutamide on blood glucose lowering effect)
To 10-week-old male db / db mice grouped according to satiety blood glucose level, 0.5% methylcellulose suspension (test compound administration group) of test compound {Appendix: Example 4-5 (5 mg / kg)}, tolbutamide 30 mg / Kg of 0.5% methylcellulose suspension (tolbutamide administration group), 0.5% methylcellulose suspension of test compound and 0.5% methylcellulose suspension of tolbutamide 30 mg / kg simultaneously (test compound and tolbutamide combination group) or 0.5 Only% methylcellulose solution (control group) was orally administered.

  Blood collection was performed under fasting conditions. That is, the fasting condition was started by removing food simultaneously with the administration of the test compound, and blood was collected from the orbital vein under anesthesia 5 hours after administration. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose kit). In the evaluation, the rate of decrease in blood glucose level in each of the other groups relative to the control group was shown in%. The results are shown in Table 12.

Test Example 6 (Effect of combined use with nateglinide on blood glucose lowering effect)
To 10-week-old male db / db mice grouped according to satiety blood glucose level, 0.5% methylcellulose suspension of test compound {Appendix: Example 4-5 (5 mg / kg)} (test compound administration group), nateglinide 30 mg / Kg of 0.5% methylcellulose suspension (nateglinide administration group), 0.5% methylcellulose suspension of test compound and 0.5% methylcellulose suspension of nateglinide 30 mg / kg simultaneously (test compound and nateglinide combination group) or 0.5 Only% methylcellulose solution (control group) was orally administered.

  Blood collection was performed under fasting conditions. That is, the fasting condition was started by removing food simultaneously with the administration of the test compound, and blood was collected from the orbital vein under anesthesia 2 hours after administration. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose kit). In the evaluation, the rate of decrease in blood glucose level in each of the other groups relative to the control group was shown in%. The results are shown in Table 13.

Test Example 7 (Effect of combined use with metformin hydrochloride on blood glucose lowering effect)
10-week-old female ob / ob mice grouped according to satiety blood glucose level, 0.5% methylcellulose suspension of test compound {Appendix: Example 4-2 (1 mg / kg)} (test compound administration group), metformin hydrochloride 30 mg / kg 0.5% methylcellulose suspension (metformin administration group), both 0.5% methylcellulose suspension of test compound and 0.5% methylcellulose suspension of metformin hydrochloride 30 mg / kg simultaneously (test compound and metformin combination group) Alternatively, only 0.5% methylcellulose solution (control group) was orally administered.

  Blood collection was performed under fasting conditions. That is, the fasting condition was started by removing food 3 hours before administration of the test compound, and blood was collected from the orbital vein under anesthesia 3 and 5 hours after administration. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose kit). In the evaluation, the rate of decrease in blood glucose level in each of the other groups relative to the control group was shown in%. The results are shown in Table 14.

Test Example 8 (Effect of combined use with voglibose on blood glucose lowering effect)
9-week-old female ob / ob mice grouped according to satiety blood glucose level were treated with 0.5% methylcellulose suspension of test compound {Appendix: Example 4-2 (1 mg / kg)} (test compound administration group), voglibose 0. 3 mg / kg 0.5% methylcellulose suspension (voglibose administration group), 0.5% methylcellulose suspension of test compound and 0.5% methylcellulose suspension of voglibose 0.3 mg / kg simultaneously (test compound and voglibose combination group) ) Or 0.5% methylcellulose solution alone (control group) was orally administered, and 1 g later, 2 g / 5 mL / kg sucrose was loaded.

  Blood collection was performed under fasting conditions. That is, the fasting condition was started by removing food simultaneously with sucrose loading, and blood was collected from the orbital vein under anesthesia 1 and 2 hours after loading. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose kit). In the evaluation, the rate of decrease in blood glucose level in each of the other groups relative to the control group was shown in%. The results are shown in Table 15.

Test Example 9 (Effect of combined use with pioglitazone hydrochloride on blood glucose lowering action)
To 8 week old male db / db mice grouped according to satiety blood glucose level, test compounds {Note: Example 4-5
(10 mg / kg)} 0.5% methylcellulose suspension (test compound administration group), pioglitazone hydrochloride 3 mg / kg 0.5% methylcellulose suspension (pioglitazone administration group), test compound 0.5% methylcellulose suspension and pioglitazone hydrochloride Both 3 mg / kg 0.5% methylcellulose suspension were orally administered simultaneously (test compound and pioglitazone combination group) or 0.5% methylcellulose solution alone (control group) once a day for 3 days.

  Blood collection was performed under fasting conditions. That is, the fasting condition was started by removing food simultaneously with the administration of the test compound, and blood was collected from the orbital vein under anesthesia on the first day of administration and 3 hours after administration. After blood collected in this manner was centrifuged, the blood glucose level was measured from the obtained plasma using the hexokinase method (glucose kit). In the evaluation, the rate of decrease in blood glucose level in each of the other groups relative to the control group was shown in%. The results are shown in Table 16.

  The NMR data of the example compounds are shown in the following table.

Claims (7)

  A pharmaceutical composition for inhibiting receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic drug for hyperlipidemia.   A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for diabetes.   A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for obesity.   A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for hypertension.   A pharmaceutical composition for inhibiting a receptor tyrosine kinase negative regulator, which is used in combination with a therapeutic agent for thrombosis. Formula [II]

[Where,
Y ¹⁰⁰ represents —C (R ¹³ ) (R ¹⁴ ) — (R ¹³ and R ¹⁴ each independently represent a hydrogen atom, a C _1-4 alkyl group, or together with the carbon atom to which they are bonded. To form a C _3-7 cycloalkane, or together with the carbon atom to which they are attached, at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom Which may contain a 5- to 7-membered heterocycle which may be contained);
R ¹⁰⁰ represents a hydroxyl group or a halogen atom;
B represents an aryl group or an aromatic heterocyclic group;
V represents = N- or = CH-;
W represents -S- or -O-;
R ³ is
(1) hydrogen atom,
(2) a halogen atom,
(3) a C _1-8 alkyl group,
(4) a C _1-6 alkoxy group,
(5) a C _1-6 alkylamino group,
(6) a di (C _1-6 alkyl) amino group,
(7) cyano group,
(8) Nitro group,
(9) a C _1-4 haloalkyl group,
(10) -S-R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group),
(11) -SO-R ¹⁸ (R ¹⁸ represents a C _1-6 alkyl group or an aryl group),
^{_{(12) -SO 2 -R 18 (}} R 18 represents a _{C 1-6} alkyl group or an aryl group),
(13) an aryl group or
(14) A heterocyclic group. Or a pharmaceutically acceptable salt thereof. In the general formula [II], R ¹³ and R ¹⁴ each represent a hydrogen atom, V represents ═CH—, and W represents —S—, or a pharmaceutically acceptable compound thereof. Possible salt.