TW201212913A - Novel hydantoin derivative and medicine using the same as effective ingredients - Google Patents

Abstract

The present invention provides a compound with stronger AMPK (adenosine monophosphate-activated protein kinase) activation effect, and exhibits beneficial effect originated from AMPK activation effect in living bodies, and also presents excellent hypoglycemic and hypolipidemic effects in living bodies. The present invention relates to a hydantoin derivatives represented by general formula (1), or a pharmacologically permissible salt or a hydrate for the same. The present invention may be applied as a human AMPK activation drug and provide effective treatment for lipid metabolism disorder or diabetes.

Description

201212913 VI. Description of the Invention: [Technical Field to Be Invented by the Invention] a The present invention relates to an endogenous urea derivative and an addition salt thereof which are effective for the treatment of abnormal lipid metabolism or diabetes, etc., as an active agent for human bribery A pharmaceutical composition containing such compounds. [Prior Art] In recent years, due to changes in lifestyles, the obese population has increased, and the so-called metabolic syndrome (metabolic abnormality) which is accompanied by a lifestyle-related disease represented by hyperlipidemia, hyperglycemia (diabetes) or hypertension Symptoms) The increase in patients is becoming a serious social problem. The reason for this is that the above-mentioned lifestyle-related diseases are major risk factors for arteriosclerosis, which are causes of myocardial infarction, angina pectoris, or stroke, and patients with metabolic syndrome of these diseases are prone to develop and develop arteriosclerosis. The cause of the disease is visceral fat obesity, abnormal lipid metabolism, abnormal glucose metabolism, or abnormal a pressure (Non-Patent Document 1). Therefore, it is expected that such lifestyle-related diseases can be prevented by improving energy metabolism abnormalities. Under this circadian month, for the treatment of diabetic patients with hyperlipidemia and patients with abnormal glucose-burning abnormalities, drugs that control the sugar value and the blood stasis agronomy are currently used. As a drug for controlling the blood sugar level, a general-purpose turtle urea-based drug, a tetrahydrothiazole-based drug, or a double-pulse-based drug is used. However, in the use of such agents, side effects such as hypoglycemia, cardiac hypertrophy, edema, or lactic acidosis are reported. In addition, as a drug for controlling the lipid concentration in a 'general fiber fibrate agent or statin (four) (four) is 158356.doc ^ 201212913, but reported gastrointestinal damage, sputum liver function from b know injury or kidney Side effects such as functional impairment. Further, in the combined therapy, there is a problem of side effects caused by the interaction between the respective drugs, and the treatment of hyperlipidemia of the diabetic patient receiving the drug treatment is not sufficiently performed. _, it is expected to develop a drug having a high control effect of blood sugar level and blood lipid concentration and excellent safety. On the other hand, research on the mechanism of energy metabolism, obesity, or diabetes has progressed, and it has been confirmed that AMPK (AMP_activated pr〇tein kinase, adenosine monophosphate-activated protein kinase) plays an extremely important role (Non-Patent Document 2). It is known that AMPK is a protein that is widely present in living organisms such as muscles and livers, and its activity is increased in the presence of ATp (Aden〇sine_ triphosphate) in the cells, and a metabolic sensor that promotes metabolism and promotes ATP synthesis is known. The function. However, according to recent research, it is considered that AMPK is not regulated only by the energy level in the cells, but also by fat cells, such as muscle movement, leptin (Non-patent Document 3), and adiponectin. The hormone (Non-Patent Document 4) or the like is activated, and is an intracellular vehicle which is caused by such fatty acid oxidation or glucose utilization promoting action. For example, AMPK is known to have an effect on the oxidation of fatty acids in mitochondria by controlling the activity of ACC, Acctyl-CoA Carboxylase. Thus, it is considered that AMPK not only activates in the absence of energy in the cells, but also plays an important role in the energy metabolism or nutrient metabolism of the organism. 158356.doc 201212913 Therefore, activation of AMPK is associated with abnormal glucose metabolism or abnormal lipid metabolism, and is a suitable molecular target for the prevention of obesity or diabetes. As a compound which activates AMPK, in addition to the above-mentioned hormone derived from an adipocyte, it is known as a therapeutic drug for diabetes, which is known as a therapeutic drug for diabetes (Non-Patent Document 5) or AICAR (Aminoimidazole Carboxamide Ribonucleotide). ). However, hormones derived from fat cells are not stable in terms of metabolism and chemistry, and cannot be provided as medicine. Further, the AMPK activation of metformin is weak, and side effects such as gastrointestinal damage or lactic acidosis have been reported, and there are problems in therapeutic effects or safety. On the other hand, as compounds which report activation of AMPK, compounds of the formulae (A) to (Q) described in Table 1 are known, but none of them have a benzyl carbendazim structure, and the structure and the present invention are The compounds are different. [Table 1] Patent Document Patent Document Type 1 Rj-Y^X^R, Office (Λ, 11 (R, 幽'" 2 翁ΐ (Β) 12 ～ 14 Rt CK) 3 R2 Rj °^rs < 〇15 ' 16 (L) 4 r2 o^X (D) 17 NH2 N person N Rl, N sense N person r2 r3 (M) 5, 6 (four) side and AH (E) 18 (N) § 158356.doc 201212913 7 (F) 19 (Ο) 8 20~23 4 (P) 9 2 (H) R'iS^x,, z Nine R5 CQ) 10 (I) Also, for isophthalonitrile such as DNP-60502(R) The furanone derivative is also reported to have AMPK activation (Non-Patent Document 6). However, the isobenzopyranone derivatives do not have a benzyl ethyl carbazide structure, and the structure is different from that of the compound of the present invention. ]

Further, Patent Document 24 discloses a compound represented by the formula (s) having an anticancer action. However, the subgingival derivatives of the B. cerevisiae described in the specification are completely different from the compound of the present invention, and the AMPK activation is completely undescribed. [Chemical 2]

In the formula (S), 'R! represents an aromatic group or a heterocyclic group, and X and γ are each independently, and represent an oxygen atom, a sulfur atom or a stretching group, and A represents an aromatic group, and a single 158356.doc -6 - 201212913 a ring or a heterobicyclic ring, D represents a phenyl group or a 6- or 5-membered heterocyclic group, e represents a phenyl group, a pyridyl group or a pyrimidinyl group, and L represents _C(〇)..._s(〇)2 or _n(R6) C〇_ a). [3], etc., 'j, m, n, p, respectively represent 〇 or 丨, τ denotes the general formula (τ_)

In the formula (T-a), R_4 independently represents a hydrogen atom, an alkyl group or the like. Further, Patent Document 25 discloses a compound represented by the formula (U) having a factor Xa inhibitory action. However, the compound described in the specification does not contain the carbendazole derivative, and it has no consumption of AMPK activation. [Chemical 4]

In the formula (U), D and D represent a hydrogen atom, a cyano group, etc., and R1 represents a hydrogen atom, a functional atom or the like. R2 represents a hydrogen atom, =0, a C?-4 group, etc., and R2 does not exist or R2a—and represents a benzene ring or the like which may be substituted by 0 to 2 R1G, R 3 and R 3 represent a gas, a pyridyl group of C i ], a phenyl group, and a Z represents a bond or an alkyl group of ο!·*. , A represents a hydrocarbon ring which may be substituted by 0 to 2 R6, B represents XY, C〇NR3R3', etc., and X represents _C(0)NR3-, -NR3C(0)-, etc., Y 158356.doc 201212913 A hydrocarbon ring of C3-1() substituted by 0 to 2 R6 of C3-1(), R6 (CH2)nOR3, (CH2)rR3R3', etc., R10 represents a hydrogen atom, a halogen atom. Patent Document Patent Document 1: International Publication No. 2004/034960 Patent Document 2: International Publication No. 2004/043957 Patent Document 3: U.S. Patent No. 2005038068, Patent Document 4: International Publication No. 2006/071095 Patent Document 5: International Publication No. 2007/002461 Patent Document 6: International Publication No. 2007/005785 Patent Document 7: International Publication No. 2007/062568 Patent Document 8: European Patent Application Publication No. 1754843 : International Publication No. 2008/006432 Patent Document 10: International Publication No. 2008/016278 Patent Document 11: International Publication No. 2008/133441 Patent Document 12: International Publication No. 2008/083124 Patent Document 13: International Publication No. 2009/ Japanese Patent Publication No. 2009-06513, Patent Document No. 1: International Publication No. 2009/019143, Patent Document No. No. 2009/019445, Patent Document No. 2009-019446, Patent Document No. 2009-019446, Patent Document No.: International Publication No. 2009/028891 18: International Publication No. 2009/100130 Patent Document 19: International Publication No. 2010/07301 Patent Document No. 20: International Publication No. 2010/036613 No. 158356.doc 201212913 Patent Document 21: International Publication No. 2010/047982 Patent Document 22 : International Publication No. 2010/051206 Patent Document 23: International Publication No. 2010/051176 Patent Document 24: International Publication No. 2004/060305 Patent Document 25: International Publication No. 1997/038984 Non-Patent Document Non-Patent Document 1: The Medical Journal of Australia, Vol. 185, No. 8, pp 445-449, 2006 Specialized in 1J Literature 2 : Molecular Medicine, Vol. 39, No. 4, pp 398-407, 2002 Guided Life 1J Literature 3 : Nature, Vol. 415, Pp 339 -343, 2002 Special Spear 1J Document 4 : Nature, Vol. 423, pp 762 -769, 2003 Non-Patent Document 5: J. Clin. Invest., Vol. 108, pp 1167-1174, 2001 Non-Patent Document 6 237th American Chemical Society National Meeting (March 22-26, Salt Lake City) 2009, Abstract MEDI 196 SUMMARY OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a compound having a chemical structure different from the above-mentioned known compounds It has a strong AMPK activation effect and exhibits an advantageous effect derived from AMPK activation in vivo. MEANS FOR SOLVING THE PROBLEMS The inventors of the present invention have focused on the specificity of energy metabolism of human AMPK in order to create a novel drug which is effective in the production of a sputum-type diabetes drug, and which has a high continuation and safety of 158356.doc 201212913. Sexual effect, repeated efforts to study, and found that the novel benzyl ethyl uregar urea derivative and its addition salt of the present invention have excellent human AMPK activation and exhibit excellent hypoglycemic action in vivo and Reduce blood fat. That is, the present invention is as follows. 1_ an endogenous brewing gland derivative or a pharmacologically acceptable salt thereof or a hydrate thereof, which is represented by the formula (1), [Chemical 5]

a cycloalkyl group having a substituent, a c6-Ci〇 aryl group which may have a substituent, a C: 7-Ci2 aralkyl group which may have a substituent, an aromatic heterocyclic ring of 5 or 6 members which may have a substituent a condensed heterocyclic group which may have a substituent, X represents a C丨~C4 alkylene group, a C2~C4 alkylene group, a C2~C4 stretching alkynyl group or a formula (2), and Y represents a single bond, C丨~ C4 alkyl or formula (5), Z represents a hydrogen atom, a halogen atom, a to G group which may have a substituent, a C3 to C6 cycloalkyl group which may have a substituent, and a c group which may have a substituent ~c6 alkoxy group, which may have a substituent: <:3~. A 6-cycloalkoxy group, a hydroxyl group, a nitro group, a cyano group, an amine group which may have a substituent, and a C6 to Ci which may have a substituent. An aryl group, an aromatic heterocyclic group of 5 or 6 members which may have a substituent, a condensed heterocyclic group which may have a substituent of 158356.doc 201212913, a c7-Ci2 aralkyl group which may have a substituent, may have a substituent a C6~C1() aryloxy group, a c7~Ci2 aralkyloxy group which may have a substituent, a C!~C6 alkylthio group which may have a substituent, a c6~Ci〇 arylthio group which may have a substituent or may be a C7-C12 aralkylthio group having a substituent, and the ring A and the ring B are the same or different and represent a c3 to c6 cycloalkyl group which may have a substituent, a 5-membered or 6-membered saturated heterocyclic group which may have a substituent, A C6-C 1 aryl group which may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent, and R 2 and R 3 are the same or different ' represents a hydrogen atom a Ci~C6 alkyl group which may have a substituent, a C3~C6 cycloalkyl group which may have a substituent, a C6~C! anthracene group which may have a substituent or a C which may have a substituent; 7~Cu arylalkyl group , or R2 and R3 are bonded to each other and are bonded to the carbon atom bonded to R2 and R3 to represent the general formula (6)], [R6], rA, u〆(2) [In the formula (2), T represents a single bond, CrC4 alkylene , c2 to C4 is an alkenyl group or a C2 to C4 alkynyl group; U represents a single bond, a Cl~C4 alkyl group or a C2~C4 stretching group; A represents a condensed group, an oxygen atom, and -S(0)p-( p represents an integer selected from 〇~2), -NR4-(R4 represents a hydrogen atom, an alkyl group which may have a substituent, a C7-Ci2 aryl group which may have a substituent, and a c6-C1G aryl group which may have a substituent a CfCe aliphatic fluorenyl group which may have a substituent, a Cl~c6 alkylsulfonyl group which may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed impurity which may have a substituent Ring group), -N(R5)S〇2-, _so2n(r5xr5 158356.doc *1) * 201212913 represents a hydrogen atom, a Ci~C6 alkyl group which may have a substituent or a C7~C!2 which may have a substituent Aralkyl group, formula (3) or formula (4)] 化, ιΛν〆(3) R5 [In the formula (3), L1 represents a single bond, an oxygen atom or _NR5·, and R5 represents The same meaning as the above] [Chemical 8] Ο , human L, (4) R5 [In the formula (4), L2 represents a single bond or an oxygen atom, and R5 represents the same meaning as the above] [Chemical 9] - ( CH2) h -Q1_(CH2) j - (5) [In the formula (5), Q1 represents an oxygen atom, -S(0)q-(q represents a selected from An integer of 〜2), -NR6- (R6 represents a hydrogen atom, a Cl~c6 alkyl group which may have a substituent, C. which may have a substituent; a Ci2 aryl group, a c6~c10 aryl group which may have a substituent An aliphatic fluorenyl group which may have a substituent, a Cj-C:6 alkylsulfonyl group which may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensation which may have a substituent Heterocyclic group) or carbonyl group, h and j are the same or different and represent an integer of 0 to 2] 158356.doc •12- 201212913 [化ίο]

[In the formula (6), Q2 represents a single bond, a fluorenylene group, an oxygen atom, _s(〇)r (r represents an integer selected from 0 to 2) or _NR7- (R7 represents a hydrogen atom, may have a substituent An alkyl group, a q~Ci2 aralkyl group which may have a substituent, a C6~C1Q aryl group which may have a substituent, a Cl~c6 aliphatic fluorenyl group which may have a substituent, and a c丨~C6 alkyl group which may have a substituent Further, a fluorenyl group, an aromatic heterocyclic group which may have a substituent of 5 or 6 members or a condensed heterocyclic group which may have a substituent), m&n identical or different represents 1 or 2]. 2. The uret urea derivative according to Item 1 or a pharmacologically acceptable salt thereof or a hydrate thereof, wherein in the above formula (", χ represents a Ci~C4 alkyl group or a formula (2a) ), [11] %Τ1 A'U1^ (2a) [In the formula (2a), T1 represents a single bond or a Ci~C4 alkyl group, U1 represents a single bond or an alkyl group, and A1 represents an oxygen atom or a sulfur atom. , _NR4a_ (R4a represents a hydrogen atom, a Cl~C6 alkyl group which may have a substituent or a c7~c12 aralkyl group which may have a substituent), -N(H5a)S〇2-, -S〇2N (R5aMR5a represents hydrogen An atom or a CrC6 alkyl group which may have a substituent or a C7 to Cl2 aralkyl group which may have a substituent), a formula (3a) or a formula (4a)]

•S 158356.doc -13- 201212913 0,1> 儿广R5a [In the formula (3 a), the meaning of B 1] [Chemical 13] Ο, human R5a (3a) represents a single bond or -NR5a-, R5a represents In the same manner as the above (4a), [in the formula (4a), the _ table does not have the same meaning as the above]. 3. The hydrate of the genus B. sylvestris or its pharmacologically acceptable salt, as described in the preceding paragraph 1 or the eve of the sulphate, the sulphate - the sulphate - the sulphate - in the above formula (1), X represents the formula (2b) ), [Chem. 14] - Τ1 - A2 - (2b) [In the formula (2b), τ! table or formula (4a)] [Chem. 15]

A single bond or a Ci~C4 alkylene group 'A2' represents a formula (3b). In the formula (3b), 'R5a represents a halogen atom or an alkyl group which may have a substituent or a C7~(:丨2 aralkyl group which may have a substituent) Base, R5a represents the same meaning as the above] I58356.doc 201212913 [Chem. 16]

(4a) [In the formula (4a), the ruler 53 indicates the same meaning as the above]. 4. The intramethanol urea derivative or a pharmacologically acceptable salt thereof or the hydrate thereof according to any one of the above items 1 to 3, wherein in the above formula (1), Z represents a hydrogen atom, An atom, a C1-C6 alkoxy group which may have a substituent, a C3 to C6 cycloalkoxy group which may have a substituent, a nitro group, a cyano group, an amine group which may have a substituent, and a C 6 to C which may have a substituent a 1Q aryloxy group, a c7~c12^ gas-burning group which may have a substituent, a thiol group which may have a substituent, a C6~C1() arylthio group which may have a substituent or may have a substituent C7~Ci2 aralkylthio group. 5. The carbendazole derivative of any one of the above items 1 to 4, or a pharmacologically acceptable salt thereof, or a hydrate of the above, wherein in the above formula (1), ring A and ring B are the same Or different, which means a C3~&cycloalkyl group which may have a substituent, a C6~C1Q aryl group which may have a substituent, a 5-membered or 6-membered saturated heteropoly group which may have a substituent, and 5 which may have a substituent An aromatic heterocyclic group of 6 members or a condensed heterocyclic group which may have a substituent. 6. The carbendazole derivative or a pharmacologically acceptable salt thereof or a hydrate thereof according to any one of the above items 1 to 5, wherein in the above formula (丨), 璟A represents a formula (7) ), [Chem. 17] 158356.doc -15- (7) 201212913

In the formula (7), V1, V2, V3 and V4 are the same or different and each represents a nitrogen atom or c-R8 (R8 represents a hydrogen atom, a halogen atom, a C!~C6 炫 group which may have a substituent, and a C3 which may have a substituent a -c6 cycloalkyl group, a Ci-Ce alkoxy group which may have a substituent, a C3~(:6 cycloalkoxy group, a hydroxyl group, a nitro group, a cyano group, a hydroxycarbonyl group, an alkoxycarbonyl group which may have a substituent An amine group having a substituent, a C6-C1Q aryloxy group which may have a substituent, a C7-aralkyloxy group which may have a substituent, a Cl~c6 alkylthio group which may have a substituent, and a C6~ which may have a substituent a C1Q arylthio group or a c7~c 2 aralkylthio group which may have a substituent). 7. A carbendazim derivative or a pharmacologically acceptable salt thereof or a hydrate thereof Formula (la), [Chem. 18] 0

(1a) [In the formula (la), Rla represents a halogen atom, a C1 to C6 alkyl group which may have a substituent, a C3 to C6 cycloalkyl group which may have a substituent, a C0 to C10 aryl group which may have a substituent or may be a C7-C12 aralkyl group having a substituent, ^ represents a formula (2c), and 丫& represents a single bond, a methylene group, an oxygen atom, a sulfur atom or NR6a_ (R6a represents a hydrogen atom or may have a substituent C)丨~C6 alkyl), 15S356.doc -16·201212913 z represents a hydrogen atom, a Cl~c6 alkoxy group which may have a substituent, a C3~C6 cycloalkoxy group which may have a substituent or a c6 which may have a substituent ～c1G aryloxy, A represents a C6~c1G aryl group which may have a substituent or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent, and Ring B represents a C which may have a substituent: 3 to C6 a cycloalkyl group, a 5-membered or 6-membered saturated heterocyclic group which may have a substituent, a C6-CiQ aryl group which may have a substituent, or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent.

R2W (5) or different, which represents a hydrogen atom, a C- to C6 cyclodecyl group which may have a substituent, or may have a substituent. The aryl group ' or R, R3a is bonded to the carbon atom bonded to R2a and 0, and represents a formula (6a). [Chem. 19] A T2 - A3 - (2c) [In the formula (2c), T2 represents Single bond or 5 trial A 3 ± 戎 fluorene, A represents general formula (3c) or general formula (4b)] [Chemical 20]

NIR CROA - (3C) [In the formula (3c), R1R5b·same or different 'is a hydrogen atom or a Ci-Ce ** group which may have a substituent) [Chem. 21]

158356.doc .17. S 201212913

(4b) (4b) [In the formula (4b), R5b represents the same meaning as the above] [Chem. 22]

[In the formula (6a), Q2a -NR7a-(R7a represents no | (6a) represents a single bond, a methylene group, an oxygen atom, a sulfur atom, -NR - (R represents a hydrogen atom or may have a substituent iCi~C6 alkane The base η is the same or different and represents 1 or 2]. 8. The uret urea derivative according to the above item 7, or a pharmacologically acceptable salt thereof or a hydrate thereof, which is represented by the formula (lb), ]

[In the formula (lb), Rlb represents a hydrogen atom, a Cl~C6 alkyl group, a C3~C6 cycloalkyl group or a formula (8)'

Xb represents a general formula (9), a general formula (1〇) or a general formula (11), and 丫1> represents an oxygen atom or a sulfur atom,

Zb represents a hydrogen atom or (^~(^ alkoxy group, ring Ab represents a C6~Ci〇 aryl group or a ratio of a bite group, and ring # represents 158356.doc -18 - 201212913 (1) c3~(:6 cycloalkyl group And (2) a piperidinyl group which may be substituted with a C- to ce alkyl group, a C1 to C6 aliphatic fluorenyl group or a c2 to C7 alkoxycarbonyl group, or (3), a 'j-a atom, a Ci~C6 Affiliation, alkoxy group, C2~C7 oxooxycarbonyl group, cyano group, c6~c1() which can be substituted by 1 or 2 (^~(^)-substituted amine group, hydroxycarbonyl group or amine carbonyl group The aryl group, R2b&R3b is the same or different and represents a hydrogen atom, (^~(:6 alkyl, C6~C10 aryl or formula (12), or "^ is bonded to the ruler 315 and bonded to R2b&R3b The carbon atom together represents the formula (6b)] [Chem. 24] —(CH2)v-r9 (8) [In the formula (8), R9 represents a hydroxyl group, a C7~C 2 aralkoxy group or a 3~6 The cyclic amine group 'v represents an integer of 1 to 6] [Chem. 25]

[化 27] 0

(11) 158356.doc -19- 3 201212913 A *(CH2)w-R10 (12) In the formula 2, 'Rl〇 represents a hydroxycarbonyl group or a c8~Cl3 aralkoxycarbonyl group' w represents 1 An integer of ～6] [Chem. 29] °H?y (6b) [In the formula (6b) and n represents the same meaning as the above]. 9. The uret urea derivative according to the item 7 or 8 or a pharmacologically acceptable salt thereof or a hydrate thereof, which is represented by the formula (lc), [Chem. 30] (1c) R, xx〇 Jx«ioc^R, _, R3b, b [In the formula (lc), Ru represents a halogen atom, a c2 to C7 alkoxycarbonyl group, a cyano group, or may be substituted by one or two Ci~C6 alkyl groups. The amine group, Rlb, R3b and Zb represent the same meaning as described above]. 10. The uret urea derivative according to the above item 1, or a pharmacologically acceptable salt thereof, or a hydrate thereof, wherein the compound represented by the above formula (1) is (R) _5-(2,4-di氧基oxy_5_propylimidazolidin-1-yl)methyl-2-methoxy-N-[4-(4-fluorophenoxy)phenylmethyl]phenylamine, (S)- 5-(2,4-di-oxyl_5-propylidene. __ι_yl) fluorenyl-2-yloxy-N-[4-(4-fluorophenoxy)phenylhydrazine Benzoylamine, 158356.doc -20- 201212913 5-(2,4-di-oxy-5,5-diamidazolidin-1-yl)indol-2-methoxy-N -[4-(4-Fluorophenoxy)phenylindolyl]benzamide, 5-(2,4-di-oxyidazolidin-1-yl)methyl-2-methoxy-N -[4-(4-fluorophenoxy)phenylmethyl]phenylguanamine, 3-(2,4-di-oxyimidazolidine-1-yl)indolyl-N-[4-(4 -fluorophenoxy)phenyl]benzamide, 5-(2,4-di-oxyidazolidin-1-yl)methyl-2-methoxy-N-[4-(4- Tributoxycarbonylpiperidin-1-yloxy)phenylindenyl]benzamide, 5-(2,4-di-oxyimidazolidine-1-yl)methyl-2-methoxy _N-[4-(4-fluorophenylthio)phenylmethyl]benzamide, 5-(2,4-di-oxyl) -8-oxa-1,3-diazaspiro[4.5]decane_1_yl)methyl-2-methoxy-N-[4-(4-fluorophenoxy)phenylmethyl Benzoguanamine, 5-(2,4-di- oxyimidazolidine-1-yl)indolyl-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide, 5-(2,4-di-oxy-3-butyl-butyl)Sodium-1-yl)methyl-2-methoxy-n_[4(4-fluorophenoxy)phenylmethyl] Benzylamine, 5-(2,4-di-oxo-3-cyclopropylimidazolidin-1-yl)methyl-2-indoleoxy_N_[4-(4-fluorophenoxy) Phenylmethyl]phenylguanamine, 5-(2,4-di-oxy-3-(2-hydroxyethyl)imidazolidinium;!-yl)methyl-2-methoxy-N- [4-(4-Fluorophenoxy)phenylmethyl]benzamide, 5-(2,4-di-oxy-3-(2-imilinylethyl)mipropene_1_ Methyl-2_methoxy-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide, or 5-(2,4-one-milk-based rice bran -1-yl)methyl_2_methoxy_n_[4_(4-cyanophenoxy)phenylindenyl]benzamide. 158. 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The above is the active ingredient. 12. The cockroach activating agent, which is the carbendazole derivative of any one of the above items (7) or a pharmacologically acceptable salt thereof or j or more of the hydrates. A hypolipidemic agent which is an active ingredient of one of the above-mentioned items 1 to 1 or any pharmacologically acceptable salt or a hydrate of the above. A prophylactic or therapeutic agent for arteriosclerosis, which is the intraglycolidine derivative of any one of the above items 1 to 1 or a pharmacologically acceptable salt thereof or one or more of the hydrates. Active ingredients. And a pharmacologically acceptable salt or one or more of the hydrates of any one of the above-mentioned items 1 to 3, or a pharmacologically acceptable salt thereof. As an active ingredient. And a pharmacologically acceptable salt or one or more of the hydrates of any one of the above-mentioned items 1 to 1 Active ingredients. A cancer therapeutic agent, which is an intracellular thyroid derivative of any one of the above items, or a pharmacologically acceptable salt thereof, or one or more of the hydrates, as an active ingredient. EFFECTS OF THE INVENTION The novel intramethylene uretide derivative and its addition salt of the present invention have excellent AMPK activation and exhibit excellent hypoglycemic action in vivo. 158356.doc -22- 201212913 and hypolipidemic action. These compounds of the present invention are effective as hypoglycemic agents and hypolipidemic agents, particularly liver blood glucose ingesting drugs and hypolipidemic drugs. [Embodiment] The compound of the present invention is a carbendazole derivative represented by the following formula (丨) or a pharmacologically acceptable salt thereof or a hydrate thereof. [化31]

, π~~~6匕 alkyl, C6~Cw aryl which may have a substituent, C7~Ci2 aralkyl which may have a substituent, 5 or 6 member aromatic heterocyclic ring which may have a substituent a condensed heterocyclic group which may have a substituent. R1 is preferably a group which may have a substituent of a nitrogen atom, a C3 to C4 alkyl group which may have a substituent, or may have a substituent in order to exhibit excellent AMPK activation. The c7-c12 aralkyl group is more preferably a hydrogen atom, a Ci~C6 alkyl group or a C3~c6 cycloalkyl group, and particularly preferably a hydrogen atom or a Ci~(tetra)alkyl group. In the formula (1), X represents C, and C4 is extended. Alkyl group, C2 to C4 alkenyl group, (: 2~(:4) alkynyl group or the following formula (2). [Chem. 32] Ά, 1) 〆 (2)

Ci~C4 stretching base, 〇2~〇4 stretching base or €(2) ' Τ means single bond C2~C4 stretching alkynyl; 158356.doc -23· 201212913 U means single bond, alkyl group or C2~(:4 is an alkenyl group; A represents a prison group, an oxygen atom, -S(0)p- (p represents an integer selected from 〇~2), -NR4-(R4 represents a hydrogen atom, may have a substituent a CpC!2 aryl group which may have a substituent, a C6~c ί aryl group which may have a substituent, a Ci~C6 aliphatic aryl group which may have a substituent, and may have a substituent (^~匸6) Alkylsulfonic acid group, 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent), -N(R5)s〇2-, _S〇2N (R^ _ (R5 represents a hydrogen atom, a C^C:6 alkyl group which may have a substituent or a C7-Ci2 aralkyl group which may have a substituent), the following general formula (3) or the following general formula (4). 33], Λ < (3) R5 In the formula (3), 'L1 represents a single bond, an oxygen atom or _nR5-, and R5 represents the same meaning as the above. [Chem. 34], N^L, (4) R5 4) where 'L2 represents a single bond or an oxygen atom, and R5 represents the same meaning as the above. X is an excellent AMPK. Of action, preferably represents an alkylene group or the following formula (2a) from 1 W 'X is more preferably represented by the following general formula (2b). [Of 35] 158356.doc • 24 · 201212913

(2a) In the formula (2a), T1 represents a single bond or C丨~C4 alkylene group, U1 represents a single bond or a Ci~C4 alkylene group, and A1 represents an oxygen atom, a sulfur atom, _NR4a- (R4a represents a hydrogen atom, a CrCs alkyl group which may have a substituent or a c7 to C12 aralkyl group which may have a substituent, -N(R5a)S〇2·, -S〇2N(R5a)- (R5a represents a hydrogen atom or may have a substituent c) to a C6-based group or a C7-Ci2 aralkyl group which may have a substituent, a formula (3a) or a formula (4a). [化36]

The meaning in the formula (3a). [37] (3a)

Lla represents a single bond or -NR&, which means the same as the above Ο R5a In the formula (4a), R5a represents the same meaning as the above. T1 - A2 - (2b) In the formula (2b), T1 represents a single bond or a Cl~C4 alkylene group, and a2 represents the following formula (3b) or the above formula (4a). ~, 158356.doc 201212913 [化39]

/N'5aR13⁄4 NIR 3b) In the formula (3b), 'Ra' represents a hydrogen atom or a Ci~c6 alkyl group which may have a substituent or a C7~C丨2 aralkyl group which may have a substituent, and R5a represents the same as the above The meaning. In the formula (1), Y represents a single bond, a Cl~C4 alkyl group or a formula (5). In order to exhibit excellent AMPK activation, Y is preferably an oxygen atom.

[Chemical Formula 40J -(CH2) h -Q1-(CH2) j - (9) In the formula (5), 'Q1 represents an oxygen atom, -S(〇)q_(q represents an integer selected from o~2), -nr6-( R6 represents a hydrogen atom, a C1 to C6 alkyl group which may have a substituent, a CpCu aralkyl group which may have a substituent, a C6 to C10 aryl group which may have a substituent, a CpCe aliphatic fluorenyl group which may have a substituent, and may have a C1 to C6 alkylsulfonyl group of a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent) or a carbonyl group, and h&j is the same or different An integer of ~2. In the formula (1), Z represents a hydrogen atom, a halogen atom, a ci~Cfi alkyl group which may have a substituent, a c3 to c6 cycloalkyl group which may have a substituent, a C1 to C6 alkoxy group which may have a substituent, and a c3~c6 cycloalkoxy group having a substituent, a hydroxyl group, a nitro group, a cyano group, an amine group which may have a substituent, a C6~c1〇aryl group which may have a substituent, and 5 members or 6 which may have a substituent Aromatic heterocyclic group. 158356.doc • 26-201212913 A condensed heterocyclic group which may have a substituent, a c7-C2 aralkyl group which may have a substituent, a C6-Cig aryloxy group which may have a substituent, May have a substituent

The CrC!2 aralkyloxy group, a fluorenylthio group which may have a substituent, a C6~c10 arylthio group which may have a substituent or a C7~Ci2 aralkylthio group which may have a substituent. z is preferably a hydrogen atom, a halogen atom, a Ci~C6 alkoxy group which may have a substituent, a C3 to C6 cycloalkoxy group which may have a substituent, a nitro group, and a cyano group in order to exhibit excellent AMPK-chemical action. An amine group which may have a substituent, a C6~CiQ aryloxy group which may have a substituent, a c7~Ci2 aralkyloxy group which may have a substituent, an alkylthio group which may have a substituent, and a C6~ which may have a substituent a C1Q arylthio group or a C7~c丨2 aralkylthio group which may have a substituent, more preferably a C丨~C6 alkoxy group which may have a substituent or a C3~C6 cycloalkoxy group which may have a substituent, and further It is preferably a Cl~C6 alkoxy group or a C3~C6 cycloalkoxy group, and particularly preferably a Cl~c6oxy group. In the formula (1), the ring A and the ring B are the same or different and each represents a C3 C6 cycloalkyl group which may have a substituent, a 5-membered or 6-membered saturated heterocyclic group which may have a substituent, and a C6~ which may have a substituent. C] an aryl group, an aromatic heterocyclic group which may have a substituent of 5 or 6 members, or a condensed heterocyclic group which may have a substituent. Ring A and Ring B are preferably the same or different in order to exhibit excellent AMPK activation, and are C3 to C6 cycloalkyl groups which may have a substituent, C6 aryl groups which may have a substituent, and 5 groups which may have a substituent A saturated heterocyclic group of 6 members or 6 members, an aromatic heterocyclic group having 5 or 6 members which may have a substituent or a condensed heterocyclic group which may have a substituent. 1A is preferably a 5-member or 6-membered saturated heterocyclic group having a substituent of 158356.doc -27·201212913, a C6-c group which may have a substituent, or may have a substituent in order to exhibit excellent AMPK activation. 5 or 6 members of the aromatic heterocyclic group are more than 2 members or 6 members of the saturated heterocyclic group, C6 to Ci. An aryl group or an aromatic heterocyclic group of 5 or 6 members, particularly preferably a c6~c1G aryl group. Specifically, the ring A is preferably, for example, the following formula (7). [化41]

(7) In the formula (7), ..., ", the same or different ' represents a nitrogen atom or c-r8 (r8 represents a hydrogen atom, a dentate atom, a Cl~Q alkyl group which may have a substituent, and a C3 which may have a substituent) a C6 cycloalkyl group, a C6 alkoxy group which may have a substituent, a C3~C6 ring alkoxy group which may have a substituent, a thio group, a nitro group, a murine group, a Zhaojik group, a CcC; An amine group which may have a substituent, a C6~CiG aryloxy group which may have a substituent, a C7~Ci 2 aryloxy group which may have a substituent, a Cl~C6 thiol group which may have a substituent, A C6-C1G arylthio group which may have a substituent or a c7-Ci2 aralkylthio group which may have a substituent). In order to exhibit excellent AMPK activation, Ring B is preferably a C6~C1() aryl group which may have a substituent, more preferably a halogen atom, a thio group or one or two (^~(:6) a C6-C1() aryl group substituted by any one of the alkyl-substituted amine groups, particularly preferably a C6-Cio aryl group which may be substituted with 1 to 3 halogen atoms. In the formula (1), R2 and R3 are the same or Different, representing a hydrogen atom, may have a substitution of 158356.doc • 28·201212913, a C-C6 alkyl group, a c3~c6 cycloalkyl group which may have a substituent, a C6~C 1() group which may have a substituent or The c7 to c12 aromatic group which may have a substituent, or the carbon atom to which R2 and R3 are bonded and which are bonded to R2 and R3, represent the general formula (6).

(6) In the formula (6), 'Q2 represents a single bond, a methylene group, an oxygen atom, -S(0)r- (r represents an integer selected from 0 to 2), and _NR7- (R7 represents a hydrogen atom, and may have a CrC6 danyl group of a substituent, a c7-C12 aralkyl group which may have a substituent, a C6-C1() aryl group which may have a substituent, an aliphatic fluorenyl group which may have a substituent, an alkyl sulfonate which may have a substituent A mercapto group, an aromatic heterocyclic group which may have a 5-member or a 6-membered substituent or a condensed heterocyclic group which may have a substituent), and m and n are the same or different and represent 1 or 2. Specific examples of the compound of the present invention include the intramethylene urea derivative represented by the following formula (la) or a pharmacologically acceptable salt thereof or a hydrate thereof. [化43]

a C3~C6 cycloalkyl group which may have a substituent, a C6~C1() aryl group which may have a substituent or a c7~c12 aralkyl group which may have a substituent, €158356.doc 29-201212913^ (2c), Ya represents a single bond, a methylene group, an oxygen atom 'sulfur atom or _NR6a_ (R6a represents a hydrogen atom or an alkyl group which may have a substituent), and za represents a hydrogen atom and a Cl~c6 alkane which may have a substituent An oxy group, a C3~C6 cycloalkoxy group which may have a substituent or a c6~c1G aryloxy group which may have a substituent, a ring Aa represents a C6-CiG aryl group which may have a substituent or a member which may have a substituent or 6-membered aromatic heterocyclic group, ring Ba represents a C3~C6 cycloalkyl group which may have a substituent, a member or a 6-membered saturated heterocyclic group which may have a substituent, and a C6~Ci〇 group which may have a substituent a 5- or 6-membered aromatic heterocyclic group which may have a substituent, R2a& R3a being the same or different, 妾& represents a non-deuterium atom, may have a substituent of Cl~c6, and a terpenes may have a substituent a C3~C6 cycloalkyl group or a C6~&aryl group which may have a substituent or a C bond with C and a carbon atom bonded to R2a and fluorene 6a). —t2-a3 (2c) Formula (4b) in the formula (2c). T represents a single bond or an anthracene group, and A3 represents a formula (3c) or a

R5b, R5b In the formula (3c), (3c) R5b and R5b' are the same or different and each represents a hydrogen atom or a c丨~c6 alkyl group which may have a substituent of 158356.doc 201212913. [Chem. 46]

(4b) In the formula (4b), R5b represents the same meaning as the above. [化47]

(6a) In the sub, m and formula (6a), Q2a represents a single bond, an anthracene group, an oxygen atom, a sulfur ^ -NR _ (Ra represents a hydrogen atom or a Ci~&alkyl group which may have a substituent) η is the same Or different means j or 2. The compound of the present invention is preferably a compound represented by the above formula (1), more preferably a compound represented by the following formula (lb), and further preferably a compound represented by the following formula Ue). [化48]

q~C6 cycloalkyl or formula (8), X is not represented by formula (9), formula (10) or formula (11), γ represents an oxygen atom or a sulfur atom, zb represents a hydrogen atom or <^~ (:6 alkoxy, 158356.doc -31- 201212913 Ring 'indicates c6~c1() aryl or pyridyl, ring "indicates (1) c3~(:6 cycloalkyl, (2) can pass C1~ C6 alkyl, aliphatic fluorenyl or c2~c7 alkoxycarbonyl

I substituted piperidinyl, or (3) may be through a halogen atom, an alkyl group, (^~(:6 alkoxy, C2~C7 alkoxycarbonyl, cyano, 1 or 2 (^~ (6-alkyl substituted amino group hydroxycarbonyl or aminocarbonyl substituted C6~C1G aryl group, R2lR3b is the same or different, represents a hydrogen atom, (^~(:6 alkyl, C6~C10 aryl, general formula (12), or the ruler 215 and 1131) are bonded and represent the general formula (6b) together with the carbon atom bonded to R2b& R3b. [Chem. 49] - (CH2)v - R9 (8) In the formula (8) R9 represents a hydroxyl group, a Cr^Cu aralkyloxy group or a cyclic amine group of 3 to 6 members, and v represents an integer of 1 to 6. [Chem. 50] 、, N人〆(9) Η Η [Chem. 51]

(1〇) [化52] 158356.doc -32· 201212913

(11) [Chemical 5 3 ] ~(CH2)w-R10 (12) In the formula (12), R10 represents a hydroxycarbonyl group or a C8-Ci3 aralkoxycarbonyl group, and w represents an integer of from 1 to 6. In the formula (6b), m and η have the same meanings as those described above. [化55] n

In the formula (lc), Rn represents a halogen atom, a c2 to c7 alkoxycarbonyl group, a cyano group, an amine group which may be substituted by one or two alkyl groups, and Rb, R2b, R and ^ represent the same as the above. meaning. The compound represented by the above formula (1) is preferably (R)-5-(2,4-di-oxy-5-propylimidazolium) from the viewpoint of excellent AMPK activation. Mercapto-2-methoxy_N_[4_(4-fluorophenoxy)phenylindolyl]benzamide, (S)_5_(2,4-dioxy-5-propylimidazolidinium -1-yl) decyl-2-decyloxy[4-(4-fluorophenyloxy)phenylmethyl]benzamide, 158356.doc -33- 201212913 5_(2'4-two-sided oxygen Base-5,5-dimethyl-m-sodium sulphate-1_yl) fluorenyl-2-methoxy-1^-[4-(4-fluorophenoxy) phenylmethyl]benzamide , 5-(2,4-di- oxyimidazolidinyl)nonyloxyl_N_[4_(4-fluorophenoxy)phenylmethyl]phenylamine, 3-(2,4- Bis-oxymymidine β-cumidin-1-yl)methyl-N_[4_(4fluorophenoxy)phenyl]benzamide, 5-(2,4-one-oxyl 0-bite- 1-based)methyl-2-decyloxy_N-[4-(4-tatabutoxymethyl-butoxy-1-yloxy)phenylmethyl]benzamide, 5- (2,4-di-side oxyimidazolidin-1-yl)methyl_2-methoxy_ν·[4_(4-fluorophenylthio)phenylmethyl]benzamide, 5-( 2,4-di-oxy-8-oxa-1,3-diazaspiro[4.5]癸·ι_基)曱基_2-曱-oxy-indole-[4-(4-fluorophenoxy)phenylindolyl]benzamide, 5-(2,4-di-oxyimidazolidinium -1-yl)methyl-Ν-[4-(4-fluorophenoxy)phenylindenyl]benzamide, 5-(2,4-di-oxo-3-butylimidazolium- 1-yl)methyl-2.methoxy-indole-[4-(4-fluorophenoxy)phenylindenyl]benzamide, 5-(2,4-di-oxy-3- Cyclopropylimidazolidin-1-yl)methylmethoxy-indole-[4-(4-fluorophenoxy)phenylidenyl]benzamide, 5-(2,4-di-oxyl) -3-(2-hydroxyethyl)imidazolidine-1-yl)methyl_2-decyloxy-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide, 5 -(2,4-di-oxy-3-(2-carbolinylethyl)imidazolidine-1-yl)methyl-2-methoxy-N-[4-(4-fluorophenoxy) Phenylmethyl]phenylguanamine or 5-(2,4-di-oxyidazolidin-1-yl)methyl-2-methoxy-N-[4-(4-cyanophenoxy) Phenylmethyl]benzamide. 158356.doc •34·201212913 Hereinafter, the definitions of the formulas of the compounds represented by the present invention will be described. Examples of the "α atom" include a gas atom, a chlorine atom, and a moth atom. Examples of the "w" include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, a:r group, or a branched carbon group. The linear cyclobutyl group such as n-pentyl or n-hexyl is exemplified as "c3~(:6-cycloalkyl)": a cyclopropyl group, a cyclopentyl group or a cyclohexyl group. :::C6~C1° aryl group' For example, a phenyl group or a naphthyl group can be exemplified by a group: a group, a naphthylmethyl group, a stupid ethyl group or a propyl group. The base, for example, n-propoxy, isopropoxy, n-butoxy:, methoxy, ethoxy, or n-hexyloxy β A, tributyloxy, n-pentyloxy can be exemplified: The propoxy group and the ring are referred to as "C3 to C6 cycloalkoxy groups", for example, an oxy group, a cyclopentyloxy group or a cyclohexyloxy group. B = 6 to c: an aryloxy group, and examples thereof include a phenoxy group. Examples of the oxygen iW oxo group include an oxy group or a benzene group as "C2~(:7 alkoxycarbonyl group), an ethoxy group or a third alkoxy group. Benzyloxycarbonyl is exemplified by a methylthio group, an ethylthio group, a group as a "C8~Cl3Moxy county", for example, as a Ci~C6 sulfur-burning group, for example, 158356.doc -35- € . 201212913 Base, n-pentylthio-n-propylthio, isopropyl sulfide For example, it can be used as a "C6-Ci arylthio group, etc.", and a phenylthio group or a naphthylthio group is used as a "C7-Ci2 arylthio group". For example, a sulfur group can be exemplified: Benzylthio or phenylethyl is exemplified as "C丨~c6 alkyl sulfinyl hydrazine", for example, a sulfinyl group or an ethyl phenyl sulfonyl group. As a "c6~c1() arylsulfinyl group" For example, a sulfhydryl group or a naphthylsulfinyl group may be mentioned. For example, a methylsulfonyl group or a "CcC6 alkylsulfonyl group", for example, an ethylsulfonyl group, for example, benzene may be mentioned. Examples of the sulfonyl group include a methylsulfonyloxy group, and examples thereof include a phenylsulfonyl group, which may be exemplified by a acetamino group as a "c6~c1()arylsulfonyl group" or a naphthyl group.醯基。 As a "C^Ce alkylsulfonyloxy" or a vinyl oxy group as a "c6~c1() arylsulfonyloxyoxy or naphthylsulfonyloxy. As "CcCe aliphatic醯基』, 基基基基基. As a "c7~c12 aromatic sulfhydryl group", for example, it can be exemplified as: a scorpion scorpion child as a "3 to 6 member of the cyclic amine group" Member And the ring group. As a "3 to 6 member of the ring-shaped nitrogen-expanding atom, 3 to 6 aziridine, a butyl bite, and "Biro," can be exemplified. &唆& Base, porphyrin 158356.doc •36· 201212913 base or thiomethym so-called “saturation of 5 or 6 members and/or saturation of 5 or 6 members of sulfur atom” is 3 with 1 upper nitrogen and oxygen Saturated heterocyclic group, for example, A ° for 4 "5 buy or 6 members of the a * J cattle. Pyrrolidin, piperidinyl, piperylene, imiline, rhyme base, Chen Jing milk Tebufenyl or pyranyl. The "aromatic heterocyclic soil of 5 members or employees" is an aromatic oxygen of 5 or 6 members containing 1 to 3 nitrogen, oxygen and/or sulfur atoms. . Examples of the "five or six members of the aromatic group" include, for example, w-. Nanji, porphinyl, "n-septidyl, imidazolyl, oxazolyl' thiazolyl, oxazolyl" , isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, yl. (4) The base of the well or the so-called "condensed heterocyclic group" is a stupid condensed ring of an aromatic heterocyclic group of 5 or 6 members, or 2 arbitrarily selected from "5 members or not" A condensed cyclic group formed by an aromatic heterocyclic ring of a squaraine heterocyclic group. Examples of the "condensed heterocyclic group" include an anthracenyl group, a benzoxazolyl group, a benzothiazolyl group, a benzofuranyl group, a benzothienyl group, a benzimidazolyl 'quinolyl group, and an isoquinolyl group. a quinazolinyl group, a quinoxalinyl group, an imidazole η-pyridinyl group, a β-pyrazolidine group or an imidazopyrimidinyl group. "CpC6 alkyl group which may have a substituent", "C3~C6 cycloalkyl group which may have a substituent", "C6~C1() aryl group which may have a substituent", C7~C which may have a substituent !2 arylalkyl group, which may have a substituent (^~〇6 alkoxy group), a C3~C6 ring alkoxy group which may have a substituent, and a C6~C1() aryloxy group which may have a substituent "C7~c12 aralkyloxy group which may have a substituent", "c2~c7 alkoxycarbonyl group which may have a substituent", "β which may have a substituent 158356.doc -37- 201212913 c8~C13 "aralkyloxycarbonyl", "CrCfi alkylthio group which may have a substituent", "c6 to c1G arylthio group which may have a substituent", "C7 to c12 aralkylthio group which may have a substituent", " (^~(:6 alkylsulfonyl), "c6~c1G arylsulfonyl group which may have a substituent", "may have a substituent

CrC6 alkylsulfonyloxy", "c6~c1()arylsulfonyloxy group which may have a substituent", "Cl~C6 aliphatic alcoholic group which may have a substituent", "C7 which may have a substituent" ~C] 2 aromatic fluorenyl group, "cyclic amine group of 3 to 6 members which may have a substituent", "saturated heterocyclic group of 5 members or 6 members which may have a substituent", "may have a substituent Examples of the "substituent" in the "aromatic heterocyclic group of 5 or 6 members" and the "condensed heterocyclic group which may have a substituent" include a halogen atom and a Cl which may be substituted by 1 to 3 halogen atoms. ~C6 alkyl, c3~C6 cycloalkyl, Ci~ alkoxy substituted by 1~3 halogen atoms, C! broad CI2 aryloxy, alkylthio, CrC6 alkyl sulfinyl, c丨~c6 alkylsulfonyl group, C2~C7 alkoxycarbonyl group, C8~Cn aralkoxycarbonyl group, hydroxyl group, nitro group, amine group which may be substituted by 1 or 2 CrC:6 alkyl groups, 3~ a 6-membered cyclic amine group, a cyano group, a hydroxycarbonyl group, a decyl group or an amine carbonyl group. The "amino group which may have a substituent" may, for example, be an amine group which may be substituted with one or two CcC6 alkyl groups, and examples thereof include an amine group, a methylamino group or a diammonium group. Examples of the "CcC4 alkylene group" include a linear or branched carbon number of 1 to 4 such as an anthracenylene group, an ethylidene group, a dimethylene group, a fluorenylethyl group or a bis-f-methylidene group. alkyl. Examples of the "C2 to C4 stretching group" include a straight chain or a branched carbon number such as a vinyl group, an extended propylene group or a methylethylene group. 158356.doc -38- 201212913 As the "CrC4 stretching alkynyl group", for example, a straight or branched carbon number such as an ethynyl group, a propargyl group or a 3-methyl-propenyl group can be cited. base. The compounds of the invention may be formulated as pharmacologically acceptable salts as desired. Examples of the pharmacologically acceptable salt include inorganic acid salts such as hydrochloric acid, hydrogen (tetra), and thioindigo, and "acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, and A. An organic acid salt such as an acid or a p-toluene core or an alkali salt such as a sodium salt, a potassium salt or a calcium salt. Further, the compound of the present invention and a pharmacologically acceptable salt thereof may be a salt thereof, an acid anhydride, a hydrate or a solvate thereof. Further, among the compounds of the present invention, optical isomers based on asymmetric carbons, such as geometric isomers, stereoisomers, tautomers, and the like, and mixtures thereof are included herein. Within the scope of the invention. The medicament of the present invention can be administered by a method such as oral or subcutaneous, intravenous or intramuscular. In order to use the compound of the present invention, a pharmacologically acceptable salt thereof or the like as a medicine, it may be in any form of a solid composition, a liquid composition or other composition, and an optimum one may be selected as needed. The medicament of the present invention can also be produced by formulating a pharmacologically acceptable carrier in the compound of the present invention. Specifically, a commonly used excipient, extender, binder, disintegrator, coating agent, sugar coating agent, pH adjusting agent, dissolving agent or aqueous or non-aqueous/mixing agent may be added, and a commonly used preparation may be added. A tablet, a pill, a capsule, a granule, a powder, a powder, a liquid, an emulsion, a suspension or an injection is prepared by a technique. The compound of the present invention has excellent sputum activation and is not particularly excellent in the organism § 158356.doc -39·201212913. It is used as an active ingredient for AMPK activating drugs, medicines, and prevention or treatment of diabetes. Use and reduce blood fat. A compound represented by the formula (1) of the compound of the present invention, a prophylactic or therapeutic agent for atherosclerosis, a prophylactic or therapeutic agent for atherosclerosis, a preventive or therapeutic agent for obesity, or a cancer, or a combination of the methods shown in the method of manufacture 1 or And manufacturing. [Manufacturing Method 1] [Chem. 56]

(15)

Μ 'W represents a leaving group, Ra represents a fluorenyl group which may have a substituent or a C7~Cu aralkyl group which may have a substituent, and R1, R2, R3, X, ^Z, ring A, and ring B are the same as above The meaning. Here, examples of the leaving group represented by W : include a dentin atom, a substituted C 1 C 6 alkylsulfonyloxy group, or a phenylsulfonyloxy group or a f phenyl fluorenyloxy group. Substituted α~~aryl group 醯: yl group and the like. 158356.doc -40-201212913 Conversion of the compound represented by the formula (13) and the compound represented by the formula (14) to the compound represented by the formula (15) (the step can be carried out as follows): In a suitable solvent, for example, in a decyl alcohol, ethanol, dichloromethane, chloroform or acetic acid or a mixture thereof, a reducing agent such as sodium triethoxy borohydride is used to obtain a formula (13). The compound represented by the formula (14) is reacted at 0 toloot for 5 minutes to 24 hours. The compound represented by the formula (16) and the compound represented by the formula (17) are introduced into the formula (15). The conversion of the indicated compound (step i_B) can be carried out by using a suitable solvent such as 'toluene, hydrazine, 4, bismuth, suffrage, bismuth, 艰 艰 Ν, Ν-dimethyl ketone or methyl, pirone or a mixture thereof, and in sodium carbonate, potassium carbonate, cesium carbonate, sodium butoxide, potassium butoxide, sodium hydride, The compound represented by the formula (16) is passed through in the presence of triethylamine, diisopropylethylamine or ton bite. The compound represented by the formula (17) is reacted at _78〇c~12 (rc under rc~100 hours). Conversion of the compound represented by the formula (15) to the compound of the formula (18) The steps are carried out by, for example, in toluene, tetrahydrofuran, dimethic acid methane, murine or N,N-dimethylformamide or the like, and τ I wish to cool in the presence of acridine, triethylamine and other bases, so that the ss Λ 匕 σ of the formula (15) and methyl isocyanate 'isocyanate, phenyl isocyanate or ^ ^, chaotic 1 dimethyl decyl ester and other lysate at 0 ~ 15 (TC reaction for 5 minutes ~ 48 hours. Seeking) can also be introduced into the tetrahydrofuran, I, 4-dioxane, Further, when R1 represents a hydrogen atom, it is used in a suitable solvent, for example, in 158356.doc -41·201212913 methanol or ethanol or a mixture thereof, and in the presence of an acid such as hydrochloric acid or acetic acid. The compound represented by the formula (15) is reacted with isocyanate such as sodium isocyanate or potassium isocyanate at 0 to 13 Torr. (: the reaction is carried out for 5 minutes to 12 hours. 18) Conversion of the compound represented by the formula to the compound represented by the formula (step 1-D) can be carried out by using in a suitable solvent, for example, in hydrazine, tetrahydrofuran, dichloromethane or n, n-dimethylformamide or such a mixture, and the like, if necessary, in sodium carbonate, carbonate, cesium carbonate, sodium butoxide, potassium butoxide, sodium methoxide, sodium hydride, triethyl In the presence of a base such as an amine, diisopropylethylamine or pyridine, or in the presence of an acid such as hydrochloric acid or acetic acid, the compound (IV) represented by the formula (10) is subjected to a reaction for 5 minutes to 12 hours. It is synthesized by the synthesis method shown in the production method 2 of the formula (I) which is a compound of the present invention. [Manufacturing Method 2] [Chem. 57]

158356.doc •42· 201212913 where Ri, ruler: R:

Ra, wi, x, Y, z, ring eight, ring # show the same meaning as above. The conversion of the compound represented by the formula (13) and the compound represented by the formula () to the compound represented by the formula (20) (step 2 - a) can be carried out by the same method as (4) 1-A. The conversion of the compound represented by the formula (16) and the compound represented by the formula (21) to the compound represented by the formula (2G) (step 2 - b) can be carried out by the same method as in the step 1-B. The conversion of the compound represented by the formula (2G) and the compound represented by the formula (22) to the compound represented by the formula (23) (step 2-C) can be carried out by using a solvent as appropriate In the case of, for example, indole benzene, M-dioxane, tetrahydrofuran, dimercaptosulfoxide, N,N-didecylguanamine or halopyrrolidone or the like, and in sodium carbonate, a compound represented by the formula (2〇) in the presence of a base such as potassium carbonate, carbonic acid planing, sodium butoxide, potassium butoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine The compound represented by the formula (22) is reacted at _78r to 12 Torr<t for 1 minute to 100 hours. The conversion of the compound represented by the formula (23) to the compound represented by the formula (step 2) -D) can be carried out in a suitable solvent, for example, in the form of a solution of tetrahydrofuran, tetrahydrofuran, dichloromethane, N,N-dimethylamine, sterol or ethanol or a mixture thereof. Etc., and if necessary, sodium carbonate, potassium carbonate, cesium carbonate, sodium butoxide, potassium butoxide, sodium decanoate, sodium hydride, triethylamine In the presence of a base such as diisopropylethylamine or pyridine, the compound represented by the formula (23) is allowed to be in the range of from 〇 to 130. (: the next reaction is 5 minutes β 158356.doc -43 - 201212913 - 12 hours. The compound represented by the formula (1) which is a compound of the present invention can also be synthesized by the synthesis method shown in the production method 3. Method 3] [Chem. 58]

(25) where R1, R2 have the same meanings as above.

The conversion of the ring B to the compound represented by the formula (24) and the compound represented by the formula (25) to the compound represented by the formula (1) (step 3_a) can be carried out as follows: In the solvent, for example, in toluene, hydrazine, 4-dioxanes, tetrahydrofuran, bis-indenyl or N,N-dimethylformamide, N-methylpyrrolidone or the like, and In the presence of a base such as sodium carbonate, potassium carbonate, carbon, sodium butoxide, potassium butoxide, sodium hydride, triethylamine, diisopropylethylamine or pyridine, the formula (24) is obtained. The compound represented by the compound represented by the formula (25) is reacted at _78乞~12〇t: 〇min, as a compound represented by the formula (1) of the compound of the present invention, a formula

The compound represented by Ue) can also be synthesized by the synthesis method shown in the production method 4

[Manufacturing Law 4J 158356.d〇 ( 201212913 [化 59]

(10) (1) In the formula, Rld represents a C1-C0 alkyl group which may have a substituent, a C3 to C6 cycloalkyl group which may have a substituent, a Ce~Ci() aryl group which may have a substituent, may have a substituent a C7-Cl2 aralkyl group, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent, w2 represents a leaving group, or a boronic acid, R2, R, X, Y, z, ring A, and ring B represent the same meanings as above. Here, examples of the leaving group represented by W2 include a halogen atom, a Ci-C which may have a substituent: a 6-alkyl group, or a phenyl fluorenyloxy group or a fluorenyl phenyl group. The C6~Cl0 aryl group which may be substituted by a lower alkyl group, and the like. The conversion of the compound represented by the formula (Id) and the compound represented by the formula (26) to the compound represented by the formula (le) (step 4-A) in the case where W2 represents a leaving group can be Step 3-A is carried out in the same manner. Further, the case where boric acid is represented by W2 can be carried out by using a solvent such as toluene, tetrahydrofuran, dichlorohydrazine, 1,2-ethanesulfur or N,N-difluorene in a suitable solvent. In the presence of a metal such as pyridine, triethylamine, 4-(dimethylamino)pyridine, sodium carbonate or carbonic acid, or a metal such as copper acetate, and if necessary, The compound represented by the formula (1) is reacted with the compound represented by the formula (26) at 0 to 150 ° C for 30 minutes in the presence of a ligand such as pyridine, triethylamine or 2,2-bipyridine. I58356.doc •45·201212913~4 8 hours 〇After the compound represented by the formula (Id) can be produced according to the production method in the case where the hydrogen atom is represented by the production method. In the compound represented by the formula (1) which is a compound of the present invention, the compound represented by the formula (If) can also be synthesized by the synthesis method shown in the production method 5. [Manufacturing Method 5] [Chem. 60]

In the formula, Aa represents an oxygen atom, a sulfur atom, or _Nr4_, and PGi represents a protecting group, and Rld, R2, R3, T, U, W1, Y, Z, ring A, and ring B have the same meanings as described above. Here, 'as a protecting group represented by PG1, a Ci~C6 aliphatic fluorenyl group which may have a substituent, (: 丨~(:6 alkoxycarbonyl group, benzyloxycarbonyl group, p-methoxybenzyl group) And the like may be a benzyl group having a substituent, a decyl group such as a trimethyl decyl group or a tert-butyl decyl fluorenyl group, or an phthalimide group or the like. 158356.doc • 46· 201212913 Self-generating (27 The conversion of the compound represented by the formula and the compound represented by the formula (10) to the compound represented by the formula Uf) (step 5_A) can be carried out by using a solvent in a suitable solvent, for example, in a suitable solvent. , tetrachloroethylene, diethyl ether, dichloromethane H methyl carbamide, N-methyl oxime, dimethyl sulfoxide or propylene _ such a mixture, etc. Potassium oxide, sodium carbonate, carbonic acid clock, gasified sodium, sodium ketone, third butanol unloading, ° bite 'triethylamine or N dimethyl aniline, etc., if necessary, add appropriate moth salt For example, a compound represented by the formula (27) and a compound represented by the formula (28) are added by adding sodium Wei, moth or mothene. The reaction of the compound represented by the formula (27a) to the compound represented by the formula (29) (step 5·Β) can be carried out by: solvent-free: _15~120〇c Or suitably, the refrigerant ten', for example, in the second gas hospital, gas imitation, four gas biting or benzene or the liquid helium, and using sulfurous chlorine, phosphorus, chlorine or sulfoxide, etc. The halogenating agent is reacted with a compound represented by the formula (27a) at _2 Torr to 8 Torr for 5 to 6 hours. Alternatively, it can be carried out by using a solvent such as a chloroform in a suitable solvent. a suitable sulfonating agent, for example, using A, in the presence of a base such as triethylamine or pyridine, or the like, in the presence of a base such as triethylamine or pyridine. The sulfonamide or the trifluoromethanesulfonic anhydride is used to react the compound represented by the formula (27a) at _2 Torr to 60 ° C for 0.5 to 3 hours. Further, it can also be carried out as follows: In the solvent, for example, in dichloromethane, chloroform or tetrahydrofuran or a mixture thereof, and in the presence of triphenylphosphine, carbon tetrabromide, four The compound represented by the formula 158356.doc •47-201212913 (2*7a) is reacted at _2〇~60°C for 0.5·3 to 3 hours by carbon chloride or iodine. The conversion of the compound and the compound represented by the formula (30) to the compound represented by the formula (If) (step 5-C) can be carried out by using a suitable solvent such as 'toluene, 1 , 4 _ 2p alkane, tetrahydrofuran, dimethyl sulfoxide 'N,N-didecyl decylamine or N-fluorenylpyrrolidone or a mixture thereof, and in sodium carbonate, carbonic acid a compound represented by the formula (29) in the presence of a base such as potassium, carbonic acid, sodium t-butoxide, potassium butoxide, sodium hydride, triethylamine, diisopropylethylamine or acridine The compound represented by the formula (30) is reacted at -78 art to 12 ° C for 1 minute to 100 hours. The conversion of the compound represented by the formula (31) to the compound represented by the formula (27) (step 5-D) can be carried out by deprotection according to a known method, for example, Protecting Groups in 〇 仏 她 _ _ [ The method described in j〇hn Wiley and S〇nsW (1999)]. For example, a method using acid, test, ultraviolet ray, hydrazine, tetrabutyl fluorinated money or trimethyl iodonane, a reduction method, or the like can be mentioned. In the compound represented by the formula (1) which is a compound of the present invention, the compound represented by the formula (10) can also be synthesized by the synthesis method shown in the production method 6. [Manufacturing Method 6] [Chem. 61]

158356.doc -48-201212913 wherein 'ring A1 represents a c6~c1G aryl group which may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent , U, Y, Z, Rld, R2, R3, and ring B represent the same meanings as described above. The conversion of the compound represented by the formula (27a) and the compound represented by the formula (3〇a) to the compound represented by the formula (lg) (step 6-A) can be carried out by using a solvent as appropriate For example, in toluene, hexane or tetrahydrofuran or a mixture thereof, diethyl azodicarboxylate or azodicarboxylic acid is used in the presence of an organic phosphorus compound such as triphenylphosphine or tributylphosphine. An electrophile such as diisopropyl ester or diazopyridine azodicarboxylate, which reacts a compound represented by the formula (27a) with a compound represented by the formula (3〇a) at 〇~6〇<t 3 to 24 hours. Alternatively, it can be carried out by using, for example, in a suitable solvent, for example, in a mixture of toluene, benzene, hexazone or tetra-n-nano or a mixture of cyanomethylene dibutyl squam or an aryl group. A phosphine compound such as methylenetrimethylsilane or the like, wherein the compound represented by the formula (27a) and the compound represented by the formula (30a) are reacted at room temperature 〜12 (rc for 2424 hours). In the compound represented by the formula (1), the compound represented by the formula (ih) can also be synthesized by the synthesis method shown in the production method 7. [Production Method 7] [Chem. 62] 158356. Doc -49- 201212913

Wherein, Ra and Rb are the same or independent, and represent a Ci~C6 alkyl group or an aralkyl group of a CpCu which may have a substituent, or a linear alkyl group of C2 to C:4 which is constituted by a combination, and Ta represents a single a bond, a Ci~C3 alkyl group, a C2~C3 alkylene group or a C2~C3 alkynyl group, ua represents a single bond, cc

C2 to C3 extend an alkenyl group, and ～, τ, υ, γ: W 1 U Υ, z ' ring A, and ring B have the same meanings as described above. The conversion of the compound represented by the formula (27b) and the compound represented by the formula (32) to the compound represented by the formula (ih) (step 7 A) can be carried out by using a solvent in a suitable solvent. 'For example, in methanol, ethanol, dioxane or chloroform or a mixture thereof, and if necessary, in the presence of an acid such as hydrochloric acid, hydrobromic acid or acetic acid or aluminum chloride or a chlorinated Lewis acid. And using a reducing agent such as lithium borohydride, sodium borohydride, sodium cyanoborohydride or sodium triethoxy borohydride to make the compound represented by the formula (27b) and the compound represented by the formula (32) at 0 The reaction is carried out at ~80 ° C for 1 to 24 hours. The conversion of the compound represented by the formula (33) and the compound represented by the formula (3〇b)m to the compound represented by the formula (1h) (step 7_B) can be carried out by the same method as in the step 7-A. get on. The compound represented by the formula (34) is converted to the compound represented by the formula (33) 158356.doc • 50-201212913 by the conversion described in, for example, Protecting Groups in Wiley and Sons (1999) (Step 7- C) can borrow

Organic Synthesis (J〇hn method, etc. is carried out by deprotection. For example, σΓ M rb -Τ- ,. Jingtian is carried out as follows: without solvent or in a suitable solvent: for example, 'in water, acetic acid, methanol, ethanol In the case of tetrahydrofuran or a mixture of the above or a mixture of hydrochloric acid, sulfuric acid or acid, the compound represented by the formula (34) is hydrolyzed under 〇~1〇〇<>c~牦 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在And in the presence of a palladium activated carbon, a palladium activated carbon _ethylenediamine complex, a platinum activated carbon, a platinum oxide or a ruthenium-supported alumina, the general formula (34) is obtained under a hydrogen atmosphere at a normal pressure of ~0.5 MPa. The compound represented by the formula (1) is a compound represented by the formula (1) which is a compound of the present invention, and the compound represented by the formula (li) can also be produced by the method of production. Synthesized by the synthesis method shown in 8. [Manufacturing method 8] [Chem. 63]

3. 158356.doc •51-201212913 indicates the same meaning as the above-mentioned β conversion from the compound represented by the formula (35) and the compound represented by the formula (3Qe) to the compound represented by the formula (ii) ( Step 8_a) can be carried out by using, in a suitable solvent, for example, in dichloro, alkane, gas, tetrahydrofuran, diethyl ether or N,N-dimethylformamide or such a mixture, And in the presence of bites, triethylamine, N-methyl phthalocyanine or 4 (dimethylamino) bite, etc., if necessary, in the presence of hydrazine hydroxybenzotriazole, N-hydroxybutyric imine Or in the presence of 3,4-dihydro-3-enzyl- 4-side oxy-oxime, 2,3-benzotrim and other reaction auxiliaries, using dicyclohexylcarbodiimide, 3_(3-di a condensing agent such as mercaptoaminopropyl)-1-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenyl azide or carbonyldiimidazole, represented by the formula (35) The compound is reacted with the compound represented by the formula (30c) at -15 to 12 Torr: 下 5 〜 5 hours. Alternatively, it may be carried out in the absence of a solvent or in a suitable solvent, for example, in toluene, tetrahydrofuran, dichlorohydrazine or N,N-dimethylamine or a mixture thereof. And, if necessary, in the presence of a base such as pyridine or triethylamine, 'use sulfoxide, sulfoxide, acetic acid or ethyl chloroacetate to make the compound represented by the formula (3 5) _15~5 Hey. The reaction is carried out for 5 minutes to 6 hours, and the carboxyl group is formed into a reactive derivative group such as a hydrazine compound, a hydrazine bromide or an acid anhydride, and then in a suitable solvent, for example, in toluene, tetrahydrofuran, dichloromethane or N, N. - dimethylformamide or a mixture thereof, etc., and represented by the formula (35) in the presence of a base such as pyridine, triethylamine or 4-(dimethylamino)pyridine The compound is reacted with a compound represented by the formula (30c) at -78 to 50 C for 15 minutes to 12 hours. 158356.doc -52-201212913 The conversion of the compound represented by the formula (36) to the compound represented by the formula (35) (step 8-B) can be carried out by: solvent-free or in a suitable solvent, For example, in water, acetic acid, methanol, ethanol, dichloromethane, tetrahydrofuran or i,4-dioxane or a mixture thereof, and using trifluoroacetic acid, hydrochloric acid, cardioic acid, etc. Lithium oxide 'Hydroxyxan' is a base such as potassium oxychloride, sodium carbonate or potassium carbonate, and the compound represented by the formula (36) is hydrolyzed at 0 to 150 ° C for 0.5 to 1 hour. Alternatively, it may be carried out in a suitable solvent, for example, in methanol, ethanol, ethyl acetate, tetrahydrofuran or N,N-dimercaptocarbamide or the like, and in palladium activated carbon. In the presence of a metal catalyst such as palladium activated carbon _ ethylene diamine complex, platinum activated carbon, platinum oxide or ruthenium-doped alumina, the compound represented by the formula (π) is subjected to a hydrogen atmosphere at a normal pressure of ~0.5 MPa. Reduction at 0 to 80 ° C for 0.5 to 12 hours. In the compound represented by the formula (1) which is a compound of the present invention, the compound represented by the formula (1j) can also be synthesized by the synthesis method shown in the production method 9. [Manufacturing Law 9J [Chem. 64]

In the formula, R1, R2, R3' R5, τ, υ, γ, z, ring A, and ring b have the same meanings as described above. 158356.doc - ϊ -53- 201212913 The conversion from the general formula (27b) and the general formula (37) to the general formula (ij) (step 9_a) can be carried out by the same method as in the step 8-A. In the compound represented by the formula (1) which is a compound of the present invention, the compound represented by the formula (lk) can also be synthesized by the synthesis method shown in the production method 10. [Manufacturing Law 10] [Chem. 65]

U, Y, Z, ring A, and ring B have the same meanings as described above. Conversion of a compound of the formula *(27) and a compound of the formula (10)) to a compound represented by the formula (ik) (step 1 (^ can be carried out by: In the solvent, for example, in the case of a phlegm and nitrogen bite 158356.doc -54 - 201212913 methane, dichlorodecane or N,N-dimethylformamide or the like, and if necessary, < In the presence of triethylamine, the compound represented by the formula (27c) is reacted at 0 to 60 ° C for 0.5 to 12 hours using a few groups of two (four). When the compound represented by (lk) is a compound wherein R5 is a hydrogen atom, the production of the compound represented by the formula (lk) (step 1〇_B) can also be carried out by using a solvent in a suitable solvent. , for example, in the presence of a compound such as pyridine or tetrahydrofuran, monooxane or N,N-dimethylformamide or the like, and if necessary, in the presence of a base such as pyridine or triethylamine, the formula (27c) The compound represented by the formula (38) is reacted for 0.5 to 12 hours under the compound k〇~6〇°c. The compound represented by the formula (lk) is Ab. In the case of a compound of _NH, the production of the compound represented by the formula (lk) (step 1 〇 -c) can also be carried out by using a suitable solvent, for example, in the presence of benzene, benzene, a compound represented by the formula (35) and a diphenyl ether, tetrahydrofuran, acetonitrile or N,N-dimethyl decylamine or the like, and in the presence of a base such as acridine or triethylamine The azide-filled diphenyl ester is reacted at 04201 for 5 to 12 hours 'after this' and then reacted with the formula (30c) at 〇~8〇°c for 1 to 12 hours. As a compound of the present invention Among the compounds represented by the formula (1), the compound represented by the formula (11) can also be synthesized by the synthesis method shown in the production method. [Production Method 11] [Chem. 66] 158356.doc - 55- 201212913

And T, U, Y, Z, ring A, and ring B represent a formula in which R1, R2, R3, and R5 have the same meanings as described above. The conversion of the compound represented by the formula (27b) and the compound represented by the formula (3〇d) to the compound represented by the formula (11) (step 11A) can be carried out by the same method as in the step 10-A. And proceed. In the compound represented by the formula (1) which is a compound of the present invention, the compound represented by the formula (lm) and the formula (In) can also be synthesized by the synthesis method shown in the production method 12. [Manufacturing Law 12] [Chem. 67]

Wherein W3 represents a halogen atom 'r, t is the same or different from 0, 1 or 2, and r+t represents 〇, 1 or 2' k represents 2, 3 or 4, R·1 , R2, R3, Y , 158356.doc • 56- 201212913 Z' ring A, ring B means the same meaning as above. The conversion of the compound represented by the formula (29a) and the compound represented by the formula (32a) to the compound represented by the formula (lm) (step 12-a) can be carried out by: first without solvent or at appropriate In the solvent, for example, in toluene, tetrahydrofuran or benzene or a mixture thereof, an organic compound such as triphenylphosphine or phosphorous Ssl diacetate is used, and the compound represented by the formula (29a) is used at -78. Reacting at -120 ° C for 1 hour to 12 hours, after which, in a suitable solvent, for example, in toluene, tetrahydrofuran, diethyl ether or dimercaptosulfoxide or a mixture of the four, and in sodium hydride, diiso In the presence of a propylamine amine, bis(trimethylsilanyl) guanamine or a third butanol, the compound represented by the formula (32a) is reacted at _78 to 12 (TC 1 to 12). Hour reaction. Conversion of the compound represented by the formula (33 a) and the compound represented by the formula (39) to the compound represented by the formula (lm) (step 12 B) can be carried out by the step 12-A. The same method is carried out. From the compound represented by the formula (1m) to the formula (ln) The conversion of the substance (step 12-C) can be carried out by using a suitable solvent such as 'in decyl alcohol, ethanol, ethyl acetate, tetrahydrofuran or chlorin or a mixture thereof. And in the presence of a palladium activated carbon, a palladium activated carbon _ ethylenediamine complex, a sulphide carbon oxidized or a carbon-catalyzed metal catalyst, under the hydrogen atmosphere of f pressure ~ 0.5 MPa, the formula (im The compound represented by the formula (5〇) is reduced by 〇·5~丨2 hours at 〇~80°c. As a compound of the present invention, the compound represented by the formula (1〇) is represented by the formula (1) The compounds can also be synthesized by the synthetic methods shown in the manufacture of clothes. 158356.doc • 57-

201212913 [Manufacturing Law 13] [Chem. 68] 〇

(CH2)rc=CH 13-A (40) Ο • • R1d , (CH2)rC=C-(丨(10) where 'Rld, R2, R3, γ, z, ring A, ring B, r And t represents the same meaning as the above. Conversion of the compound represented by the formula (29aa) and the compound represented by the formula (4〇) to the compound represented by the formula (1〇) (step 13-A) It can be carried out in a suitable solvent, for example, in the presence of terpene, tetrahydrofuran, diethyl ether, dimethyl sulfoxide or tridecyl hexamethyl phosphate or a mixture thereof, and sodium hydride. In the presence of a base such as n-butyllithium, lithium amide or potassium carbonate, if necessary, an appropriate iodide salt, for example, sodium iodide, copper (I) iodide or tetrabutylammonium iodide, etc. The compound represented by (29aa) and the compound represented by the formula (4〇) are reacted under _78~12〇 for 12 hours. In the present specification, the compound represented by the formula (16), the formula (13) a compound represented by the formula, a compound represented by the formula (25), and a compound represented by the formula (25), wherein the compound represented by the formula (25a) can be represented by a method of production. Method synthesized. 158356.doc -58- 201212913 [Production Method 14] [Formula 69]

(43) (42) wherein 'Re represents a hydrogen atom, a Cl~c6 alkyl group which may have a substituent or a c7~c12 aralkyl group having a substituent, \\^, χ, γ, ζ, ring a, ^b means the same meaning as the above. The conversion of the compound represented by the formula (41) to the compound represented by the formula (25a) (step 14-A) can be carried out by using a suitable solvent, for example, tetrahydrofuran, i, ' Dioxane, diethyl ether, decyl alcohol, ethanol or dichlorohydrazine or a mixture thereof, and using a hydrazine, a rosin-dimethyl sulfide complex, lithium aluminum hydride or diisobutyl hydrogenation A reducing agent such as aluminum is subjected to a reaction of the compound represented by the formula (9) at _78~un: for 10 hours. The compound represented by the formula (13) is carried out by converting a compound represented by the formula (41) to a suitable solvent in a suitable solvent (step 14-B) by, for example, 158356.doc •59·201212913, for example , in tetrahydrofuran, diethyl ether 'sterol, ethanol or dichloromethane, or a mixture thereof, and using a reducing agent such as diisobutylaluminum hydride, the compound represented by the formula (41) is at -78~ 60. (: the next reaction is 1 to 24 hours. The conversion of the compound represented by the formula (25a) to the compound represented by the formula (13) (step 14-C) can be carried out by: in a suitable solvent , for example, in benzene, dioxane, chloroform, acetonitrile, dimethyl sulfoxide or acetone or a mixture thereof, and with Jones reagent, PCC (Pyridinium)

Chlorochromate ’ chlorochromate pyridine salt, pDc (pyruvate)

Decarboxylase, propyl! The compound represented by the formula (25a) is allowed to react at -78 to 80 ° C for 1 to 48 hours by an oxidizing agent such as acid decarboxylase, manganese dioxide or oxalic acid (Swern oxidation). The conversion of the compound represented by the formula (13) to the compound represented by the formula (25 &) (step 14-D) can be carried out by using a suitable solvent, for example, tetrahydrofuran or dioxime. Alkane, diethyl ether, decyl alcohol, ethanol or - gas smoldering or the like, and the like, and using a reducing agent such as rotten hydrogenation, sodium hydride, hydrogenation, or diisobutyl hydrohydrazine, the general formula (1) The compound represented by the reaction at -78 to 15 (rc for 24 hours). The conversion of the compound represented by the formula (25a) to the compound represented by the formula (25) (step 14-E) can be carried out by Step 5_B is carried out in the same manner. The conversion of the compound of the formula (25a) to the compound represented by the formula (16) (step 14-F) can be carried out by, for example, in a suitable solvent. , in chlorobenzene, acetonitrile, ethylene glycol, N,N-dimethylamine, dimethyl-hard or hexamethylphosphoric acid or a mixture thereof, and in triphenylphosphine or In the presence of a tri-T base organophosphorus compound, use azo two 158356 tdoc • 60· 201212913 citrate- s s, azo dioxime An electrophilic agent such as diisopropyl g or dioxin diterpenoid bite is allowed to react with a compound represented by the formula (25a) and phthalimide or a salt thereof at 0 to 60 ° C. After 24 hours, in a suitable solvent, for example, in decyl alcohol, ethanol or tetrahydrofuran or a mixture thereof, it is reacted at 0 to 100 ° C using an acid, a base or a hydrazine or the like. The conversion of the compound represented by the formula (13) to the compound represented by the formula (16) (step i4-G) can be carried out by using a solvent such as decyl alcohol or ethanol in a suitable solvent. , in the presence of hydrochloric acid, hydrogen acid or acetic acid or acid or chlorinated or zinc chloride, etc., using a boron hydride clock, apparently in the presence of dichlorohydrin or chloroform or such a mixture. a reducing agent such as sodium nitride, sodium sulfonate or sodium triethoxy hydride hydride, such that the compound represented by the formula (Η) is reacted with an amine at a ratio of 〇 to 5 〇 5 to 24 hours, thereafter, In a suitable solvent, for example, in a dichlorocarbyl, tetrahydrofuran or ethyl drunk or a mixture thereof, The medium needs to be reacted in a hydrogen gas at a temperature of 〇~80 C for 1 to 24 hours in the presence of acetic acid or a salt acid. The second reaction can also be carried out by: converting the compound represented by the formula (1)) to an amine. Or ammonic acid methyl vinegar equals. ~6. . . The next step is in a suitable solvent, for example, 吋-&& 4 wind 11 pain, methanol or ethanol 叆

The special mixed liquid is t, so that it is combined with the material ^ U. The conversion of the compound represented by the general formula (25) (step UH) can be carried out by a compound represented by the following formula (6), for example, in chlorobenzene, acetonitrile, r / carried out: in the appropriate solvent monol, N, N-dimethylformamide, 158356.doc -61.

S 201212913 Dimethyl sulphate or trimethylamine hexamethylphosphate or a mixture thereof, such as sodium carbonate, carbonic acid unsalted, cesium carbonate, third butanol, potassium third butoxide, sodium nitride, three In the presence of ethylamine, diisopropylethylamine or _, the compound represented by the formula (25) is reacted with o-xylyleneimine or a salt thereof for 3 to 24 hours, and thereafter In a suitable solvent, for example, in methanol, ethanol or tetrahydrofuran or a mixture thereof, (4), test or tillage, etc., to make it 0 to 80. (: the reaction is carried out for 24 hours. The conversion of the compound represented by the formula (42) to the compound represented by the formula (16) (step M-Ι) can be carried out by using a solvent in a suitable solvent. 'For example, in a methanol, ethanol or tetrahydrofuran or a mixture thereof, and in the presence of ammonia or the like, a compound represented by the formula (42) is formed under a single carbon, a thunder or an oxidizing agent metal catalyst. (6) reacting with chlorine for 5 to 8 hours in 5 to 8 generations, and can be carried out by: in a suitable solvent, for example, 'ethanol tetra-negative ^" or dichlorogen or a mixture thereof In addition, an acid or a chlorinating material such as chlorinated n-sulfuric acid is added as needed, and reacted with a reducing agent such as hydrogenated lithium or sodium borohydride at Wc for 48 hours. Among the compounds represented by the formula (41), Re represents a C丨~C6 alkyl group which may have a substitution or a compound which may have a C7~C12 aralkyl group substituted for the "ρ _ ..., a hexa substituent". The conversion of a compound having no wind atom may be as follows To carry out the agent or in a suitable solvent, for example, H acetic acid, methanol, ^ 1, tetrahydrogen bite or In the case of the No. 2 or the mixed liquid, etc., the acid, the oxidation clock, the sodium hydroxide, the potassium hydroxide, the sodium sulphate or the potassium carbonate is used to make the formula (4) The compound represented by 妒158356.doc -62 · 201212913 is hydrolyzed at 〜100 ° C for 1 to 48 hours. The conversion of the compound of the genus (43) to the compound of the formula (42) is 0. It is carried out in the following manner: in a suitable solvent, for example, in water, ethanol, tetrahydrogenase, N,N-dimethylamine, N-methylamine, N-methyl Toluene or xylene or a mixture thereof, and if necessary, a ligand such as triphenylphosphine, toluene_polycyclohexylphosphine...-dimethoxybiphenyl or diphenylphosphinoferrocene, sodium carbonate In the presence of carbonic acid or triethylamine, and in the presence of metal catalysts such as tetrakis(triphenylphosphine), tris(diphenylideneacetone), acetate or copper sulfide, cyanide and iron are used. The cyanide is decomposed or cyanated, and the cyanating agent is reacted at 0 to 250 t: for 48 hours. In the present specification, the compounds represented by the formulas (13), (41) and (42) are in the formula. 44) may be a compound represented by the production method of the synthesis method in 15 synthesized. [Production Method 15] [Chemical Formula 70] Η · Α ·· υ, 15-B (46)

15-A where Γ represents fluorenyl, cyano, CO〇Ra, Aa, Ra w, Y, z, ring a, ring B have the same meaning as above (45a)

T, U 158356.doc -63- 201212913 The conversion of the compound represented by the formula (45) and the compound represented by the formula (28) to the compound represented by the formula (44) (step 15-A) This is carried out in the same manner as in the step 5-A. The conversion of the compound represented by the formula (45a) to the compound represented by the formula (46) (step 15-B) can be carried out by the same method as the compound represented by the step 5-B. The conversion of the compound represented by the formula (46) and the compound represented by the formula (30) to the compound represented by the formula (44) (step 1 5-C) can be carried out by the same procedure as in the step 5-C. The method is carried out. Among the compounds represented by the formula (44), the compound represented by the formula (44a) can also be synthesized by the synthesis method shown in the production method 16. [Manufacturing Law 16] [Chem. 71]

(45a) (44a) wherein Ja, U, Y, Z, ring A1, and ring B have the same meanings as described above. The conversion of the compound represented by the formula (30a) and the compound represented by the formula (45a) to the compound represented by the formula (44a) (step 16-A) can be carried out by the same method as in the step 6-A. get on. Among the compounds represented by the formula (44), the compound represented by the formula (44b) can also be synthesized by the synthesis method shown in the production method 17. 158356.doc -64- 201212913 [Manufacturing Method 17] [Chem. 72]

Y, Z, ring A, and ring B have the same meanings as described above. The conversion of the compound represented by the formula (45b) and the compound represented by the formula (32) to the compound represented by the formula (44b) (step 17-A) can be carried out by the same method as in the step 7-A. get on. The conversion of the compound represented by the formula (47) and the compound represented by the formula (3 Ob) to the compound represented by the formula (44b) (step 17-B) can be carried out by the same method as in the step 7-A. And proceed. Among the compounds represented by the formula (44), the compound represented by the formula (44c) can also be synthesized by the synthesis method shown in the production method 18. [Manufacturing Method 18] [Chem. 73]

158356.doc -65- 201212913 wherein, Ja, R5, Τ, U, Υ, Z, ring A, and ring B have the same meanings as described above. The conversion of the compound represented by the formula (30c) and the compound represented by the formula (48) to the compound represented by the formula (44c) (step 18-A) can be carried out by the same method as in the step 8-A. get on. Among the compounds represented by the formula (44), the compound represented by the formula (44d) can also be synthesized by the synthesis method shown in the production method 19. [Manufacturing Method 19] [Chem. 74]

The same meaning. The conversion of the compound represented by the formula (45b) and the compound represented by the formula (37) to the compound represented by the formula (44d) (step 19-A) can be carried out by the same method as in the step 8-A. get on. Among the compounds represented by the formula (44), the compound represented by the formula (44e) can also be synthesized by the synthesis method shown in the production method 20. [Manufacturing Method 20] [Chem. 75] 158356.doc •66· 201212913

(49) wherein, Ja, R5, T, U, Y, Z, ring A, ring B, and VIII15 have the same meanings as those described above. The conversion of the compound represented by the formula (30c) and the compound represented by the formula (45c) to the compound represented by the formula (4 4e) (step 20-A) can be carried out by the same method as in the step 10-A. And proceed. When the compound represented by the formula (44e) is a compound wherein R5 is a hydrogen atom, the compound represented by the formula (38) and the compound represented by the formula (45c) are represented by the formula (44e). The conversion of the compound (step 20-B) can be carried out by the same method as in the step 10-B. When the compound represented by the formula (44e) is a compound in which 八15 is -NH-, the compound represented by the formula (49) and the compound represented by the formula (30c) are given to the formula (44e). The conversion of the indicated compound (step 20-C) can be carried out by the same method as in the step 10-C. Among the compounds represented by the formula (44), the compound represented by the formula (44f) 158356.doc-67-201212913 can also be synthesized by the synthesis method shown in the production method 21. [Manufacturing Method 21] [Chem. 76]

The same meaning. The conversion of the compound represented by the formula (45b) and the compound represented by the formula (30d) to the compound represented by the formula (44f) (step 21-A) can be carried out by the same method as in the step 10-A. And proceed. Among the compounds represented by the formula (44), the compounds represented by the formula (44g) and the formula (44h) can also be synthesized by the synthesis method shown in the production method 22. [Manufacturing Law 22] [Chem. 77]

22-C

In the formula, Jb, W3, Y, Z, ring A, ring B, r, t, and k have the same meanings as those of the above-mentioned 158356.doc-68·201212913. The conversion of the compound represented by the formula (46a) and the compound represented by the formula (32a) to the compound represented by the formula (44g) (step 22-A) can be carried out by the same method as in the step 12-A. get on. The conversion of the compound represented by the formula (47a) and the compound represented by the formula (39) to the compound represented by the formula (44g) (step 22-B) can be carried out by the same method as in the step 12-A. get on. The conversion of the compound represented by the formula (44g) to the compound represented by the formula (44h) (step 22-C) can be carried out by the same method as in the step 12-C. Among the compounds represented by the formula (44), the compound represented by the formula (44i) can also be synthesized by the synthesis method shown in the production method 23. [Manufacturing Method 23] [Chem. 78]

In the formula, Ja, W3, Y, Z, ring A, ring B, r, t have the same meanings as described above. The conversion from the general formula (46b) and the general formula (40) to the general formula (44i) (step 23-A) can be carried out by the same method as in the step 13-A. 158356.doc -69-201212913 In the present specification, the compound represented by the formula in the compound represented by the formula (9) can also be synthesized by the synthesis method shown in the production method 24. [Manufacturing Method 24] [Chem. 79] 〇

R4-nh2 (50) Meaning of H^~U 24-A (27b) ua and z are the same as the above, and the compound represented by the formula (33) and the compound represented by the formula (5〇) are The conversion of the compound represented by (27b) (step 24·α) can be synthesized by the same method as in the step 7_Α. Among the compounds represented by the formula (27b), the compound represented by the formula (27e) can also be synthesized by the synthesis method shown in the production method 25. 〇 [Manufacturing Method 25] [Chem. 80]

The meanings of the above are the same as those described above. The conversion of the compound represented by the formula (51) to the compound represented by the formula (27e) (step 25-A) can be carried out by using a suitable solvent, for example, methanol 'ethanol, four Hydrogen flooding, ethyl acetate or n-two 158356.doc •70· 201212913 methyl f-amine or 兮·# ^ μ mixed liquid, etc., and in palladium carbon, Raney nickel or the first metal catalyst 匕The compound represented by the formula (51) is reacted with hydrogen under 〇~t for 1 to 24 hours. 〇 can also be carried out by: solvent-free or in a suitable sword, for example, 'in tetrahydrofuran, dioxin, f-alcohol or ethanol or a mixture thereof, and in hydrochloric acid or In the presence of an acid such as acetic acid, a compound represented by the formula (51) is used in the presence of an acid such as a reduced hydrazine or a hydrazine. (: the next reaction is 0.5 to 12 hours. In the present specification, the compounds represented by the general formulae (31), (34), (36) and (51) are contained in the compound represented by (56), and may also be borrowed. It is synthesized by the synthesis method shown in % of the manufacturing method. [Manufacturing method 26] [Chem. 81] 158356.doc

-71 - 201212913

RaO(RbO)CH_Ua-, Aa, R1, Ra, Rb, R2, R3, U, Ua, W1, Z, PG1 have the same meanings as described above. The conversion of the compound represented by the formula (52) and the compound represented by the formula (17) to the compound represented by the formula (53) (step 26-A) can be carried out by the same method as in the step 1-B. get on. The conversion of the compound represented by the formula (54) and the compound represented by the formula (14) to the compound represented by the formula (53) (step 26-B) can be carried out by the same method as in the step 1-A. get on. The conversion of the compound represented by the formula (53) to the compound represented by the formula (5 5) (step 26-C) can be carried out by the same method as the step 1-C. The conversion of the compound represented by the formula (55) to the compound represented by the formula (56) (step 26-D) can be carried out by the same method as in the step 1-D. The conversion from the compound represented by the formula (52) and the compound represented by the formula (21) to the formula (57) (step 26-E) can be carried out by the same method as in the step 2-B. The conversion from the compound represented by the formula (54) and the compound represented by the formula (19) to the formula (57) (step 26-F) can be carried out by the same method as in the step 2-A. The conversion of the compound represented by the formula (57) to the compound represented by the formula (58) (step 26-G) can be carried out by the same method as in the step 2-C. The conversion of the compound represented by the formula (58) to the compound represented by the formula (56) (step 26-H) can be carried out by the same method as in the step 2-D. Each optical isomer of the compound represented by the formula (1) can be synthesized by using the optically active starting material compound by the above production methods 1 to 26. 158356.doc •72- 201212913 In addition, we can also use the following method to synthesize the use of acid or alkali in the first step to recrystallize and separate the formula (丨) from the formula (recognition R fly 1) Spinning, or separation of Weidou by means of stepwise, day-to-day or chromatographic method, the racemic body represented by the formula (1) and the optically active alcohol-derived (four) optically active The diastereomeric steroid or (a) phase derivative obtained is subsequently hydrolyzed. It is also produced by a method of chromatography using an optically active support <1* + a 2, + . EXAMPLES The present invention will be specifically described by the following examples, but the present invention is not limited to the specific examples. <Reference Example 1 > 5-Mercapto-2-oxooxy-oxime-[4-(4-indolyloxy)phenylindenyl]benzamide [Chemical 82]

Add 5-in 5-5-yl-2-mercaptobenzoic acid (μ.6 g, 253 mmol) in Ν_methylmethanamine solution (5 〇〇mL) in an ice bath with cooling and stirring B

CHO amine (35_3 mL ' 253 mmol), ethyl chloroantimonate (25.4 mL ' 266 mmo1) and stirred for 1 〇 min under the same conditions. Then, [4-(4-fluorophenoxy)phenylindenyl]amine hydrochloride (7〇6 g' 278 mm〇1) was added to the reaction mixture under the same conditions for 20 minutes. The reaction mixture was poured into ice 158356.doc -73-201212913 in water, 1 N hydrochloric acid was added to make pH 4, and crystals of crystallization were collected by filtration. The title compound (76.7 g, 80%) was obtained. Melting point: 132-133 ° C ] IR (ATR): 3341.3, 1690.7, 1638.3, 1536.1, 1495.0 cm*1 〇JH-NMR (CDC13, 400 MHz) δ 4.04 (3H, s), 4.67 (2H, d, J=5.5 Hz), 6.92-7.06 (6H, m), 7.13 (1H, d, J=8.6 Hz), 7.33 (2H, d, J=8.6 Hz), 8.00 (1H, brs), 8.04 (1H, Dd, J=8.6, 2.4 Hz), 8.75 (1H, d, J=2.4 Hz), 9·99 (1H, s). ESIMS (+): 380.1 [M+H]+. HRESIMS (+): 380.12954 (calculated as C22H19FN04 is 380.12981). [Example 1] 5-(2,4-di-oxy-5,5-dimethylimidazolidin-1-yl)methyl-2-methoxy-N-[4-(4-fluorobenzene) Oxy)phenylmethyl]benzamide A first step 2-[3-[[4-(4-fluorophenoxy)phenylindolyl]aminoindolyl]_4_methoxyphenyl Methylamino-2-methylpropionate

Add 2-ethylamine to a solution of methyl 2-amino-2-methylpropanoate (242 mg, 1.58 mmol) in dichloromethane (5.3 mL) with ice-cooling and stirring ( 〇 22 158356.doc * 74 - 201212913 mL '1·58 mmol), the compound of Reference Example 1 (400 mg, 1.05 mmol), sodium ethoxide hydride sodium hydride (334 mg, 1.58 mmol), acetic acid (90·2 gL, 1.58 mmol) And stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and ethyl acetate (20 mL?). The base layer was combined and washed with brine (20 mL) The residue was purified by silica gel column chromatography ( EtOAc EtOAc EtOAc EtOAc EtOAc Colorless powdery crystalline IR (ATR): 3410.1, 2949.4, 1717.2, 1647.3, 1532.7, 1498.6, 1458.7, 1365.6, 1292.0, 1245.5, 1218.4, 1138.2, 1109.9 cm'1 〇! H-NMR (CDC13j 400 MHz) δ 1.36 ( 6H, s), 3.61 (2H, s), 3.75 (3H, s), 3.92 (3H, s), 4.64 (2H, d, J=5.5 Hz), 6.90-7.06 (7H, m), 7.32 (2H , d, J=9.2 Hz), 7.45 (1H, dd, J=8.3, 2.1 Hz), 8.15-8.20 (2H, m). ESIMS (+): 481.2 [M+H]+. HRESIMS (+): 481.21418 (calculated as C27H3〇FN205 is 481.21387). Second step 5-(2,4-di-oxy-5,5-dimethylimidon-1-yl)methyl-2-methoxy[4-(4-fluorophenoxy) Benzohydrazide [Chem. 84] 158356.doc -75- 201212913

Add potassium citrate (95.4 mg, 1.18 mmol) to the solution of the first step (471 mg, 0.98 mmol) in acetic acid (5 mL), stir at room temperature for 1 hour, then search at 1 〇〇C 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate (2 mL mL 2). The combined base layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography ( EtOAc EtOAc EtOAc EtOAc EtOAc 64%) °

Colorless powdery crystals Melting point: 155-156 ° C IR (ATR): 3395.9, 3199.4, 2974.4, 1768.5, 1713.9, 1662.9, 1609.7, 1532.7, 1493.9, 1428.0, 1298.3, 1247.4, 1209.3, 1135.9, 1023.6 cm-1. ^-NMR (DMSO-d6, 400 MHz) δ 1.17 (6H, s), 3.86 (3H, s), 4.41 (2H, s), 4.45 (2H, d, J=5.5 Hz), 6.95 (2H, d , J=8.6 Hz), 7.00-7.12 (2H, m), 7.33 (2H, d, J=8.6 Hz), 7.16-7.27 (2H, m), 7.32 (2H, d, J=8.6 Hz), 7.44 (1H, dd, J=8.6, 2.4 Hz), 7.75 (1H, d, J=2.4 Hz), 8.68 (1H, t, J=6.1 Hz), 10.9 (1H, s). ESIMS (+): 492.2 [M+H]+. 158356.doc -76- 201212913 HRESIMS (+): 492.19368 (calculated as C27h27FN3〇5 492.19347) ° Elemental analysis: Actual measured value C 65.96°/. , Η 5.61 %, N 8.3 7%, calculated as C27H26FN3O5 C 65.98%, 5.3 5.33%, Ν 8.55%. <Examples 2 to 5> The reaction of the compound of Reference Example 1 and the corresponding amino acid vinegar was carried out according to the method of Example 1 to obtain a compound represented by the following formula and Table 2. [化85]

Example No. 2 H Pr 3 Pr H 4 Ph H 5 CH2CH2COOB„ H

[Embodiment 2]

(S)-5-(2,4-di-oxy-5-propylimidazolidin-1-yl)indol-2-yloxy-indole-[4-(4-fluorophenoxy)benzene Phenyl hydrazide colorless powdery crystalline melting point: 65-67 ° C IR (ATR): 3383.8, 3170.8, 2959.6, 1769.3, 1713.3, 1638.1, 1529.8, 1494.5 cm·1. ^-NMR (DMSO-d6, 400 MHz) δ 0.74 (3H, t, J = 7.3 Hz), 158356.doc -77· 201212913 0.95-1.22 (2H, m), 1.58-1.68 (2H, m), 3.85 -3.90 (1H, m), 3.87 (3H, s), 4.23 (1H, d, J=15.3 Hz), 4.46 (2H, d, J=6.1

Hz), 4.57 (1H, d, J = 15.3 Hz), 6.95 (2H, d, J = 8.6 Hz), 7.08-7.06 (2H, m), 7.11 (1H, d, J=8.6 Hz), 7.16- 7.24 (2H, m), 7.33 (2H, d, J=8.6 Hz), 7.40 (1H, dd, J=8.6, 2.4 Hz), 7.68 (1H, d, J=2.4 Hz), 8.68 (1H, t , J = 6.1 Hz), 10.8 (1H, s). ESIMS (+): 506.2 [M+H]+. HRESIMS (+): 506.20894 (calculated as C28H29FN305 is 506.20912) ° Elemental analysis: Actual measured value C 65.67%, H 5.76 °/. , N 8.00%, as C28H28FN305 · 0.4H2O Calculated value C 65,59%, Η 5,66%, N 8.20%. [Example 3]

(11)-5-(2,4-di-oxy-5-propylimidazolidin-1-yl)indol-2-methoxy-:^-[4-(4-fluorophenoxy) Phenylmethyl]benzamide A colorless powdery crystal melting point: 65-68 ° C IR (ATR): 3391.0, 3 169.9, 2959.6, 1769.8, 1714.4, 1638.5, 1530.6, 1494.4 cm·1 ° !H-NMR (DMSO-d6, 400 MHz) δ 0.74 (3H, t, J = 7.3 Hz), 0.95-1.22 (2H, m), 1.58-1.68 (2H, m), 3.85-3.90 (1H, m),

3.87 (3H, s), 4.23 (1H, d, J = 15.3 Hz), 4.46 (2H, d, J=6A

Hz), 4.57 (1H, d, J = 15.3 Hz), 6.95 (2H, d, J = 8.6 Hz), 7.08-7.06 (2H, m), 7.11 (1H, d, J=8.6 Hz), 7.16- 7.24 (2H, m), 158356.doc •78- 201212913 7.33 (2H,d,]=8·6 Hz), 7.40 (1H, machine 8 6, 2 4 Hz) 7 ^ (1Η5ί1,;=2.4Ηζ ), 8.68 (1Η5ΐ, ί==6.ΐΗζ) ΐ()8(ΐΗ55);' ESIMS (+): 506.2 [Μ+Η]+. for

HRESIMS (1): 506.20945 (calculated as CH 28il29FN3〇5 506.20912) ° Elemental analysis: Actual measured value C 66.25%, H sn 乂76〆0, Ν 8·130/〇, calculated as C28H28FN305 C 66.52%, η 5 Ss. / η , Ν 8.31%.

[Example 4] (R)-5-(2,4-di-oxy-5-phenylimidazolidinyl)methyljmethoxy[4-(4-fluorophenoxy)phenylmethyl Phenylguanamine colorless powdery crystalline melting point: 83-85 ° C IR (ATR): 3388.4, 3063.5, 1771.2, 1713.2, 1639.0, 1530.1, 1493.8, 1411.9, 1297.7, 1246.1, 1209.0, 1188.6, 11〇4_3, 1014, 9, 938, 4 cm-1. [H-NMR (DMSO-d6,400 ΜΗζ) δ 3.77 (1H, d, J = 15.9 Hz), 3.85 (3H, s), 4.45 (2H, d, J = 5.5 Hz), 4.73 (1H, d, J = 15.3 Hz), 4.91 (1H, s), 6.96 (2H, d, J = 8.6 Hz), 7.00-7.07 (3H, m), 7.15-7.25 (5H, m), 7.10-7.41 (5H, m ), 7.49 (1H, d, J = 2.4 Hz), 8.66 (1H, t, J = 5.8 Hz), 11.4 (1H, s). ESIMS (+): 540.2 [M+H]+. HRESIMS (+): 540.19365 (calculated as C31H27FN305 is 540.19347) ° Elemental analysis: Actual measured value C 68.66% ' H 4.99%, N 7.64%, for 158356.doc •79- 201212913 Calculated for C3iH26FN3〇5 C 69.01 %, 4.8 4.86%, N 7.79%. [Example 5]

(R)-3-n_[3-[[4-(4-Fluorophenoxy)phenylmethyl]amine-methylpyridyl 4_methoxyphenylindenyl]-2,4-di-oxo Propionate] propionic acid gg is a colorless powdery crystalline melting point: 50-52 ° C IR (ATR): 3389.7, 3063.5, 1769.9, 1717.7, 1639.2, 1531.1, 1494.4, 1439.1, 1291.1, 1246.3, 1209.1, 1188.7, 1106.8, 1014.3 cm-1. !H-NMR (DMSO-d6, 400 MHz) δ 1.91 -2.06 (2H, m), 2.20-2.35 (2H, m), 3.85 (3H, s), 3.94 (1H, dd, J=6.1, 4.3 Hz ), 4.22 (1H, d, J-15.3 Hz), 4.45 (2H, d, J=6.1 Hz), 4.55 (1H, d, J=15.9 Hz), 5.02 (2H, s), 6.94 (2H, d , J=8.6 Hz), 6.98- 7.05 (2H, m), 7.09 (1H, d, J=8.6 Hz), 7.16-7.23 (2H, m), 7.27-7.40 (8H, m)} 7.67 (1H, d, J = 2.4 Hz), 8.67 (1H, t, J = 5.8 Hz), 11.0 (1H, s). ESIMS (+): 626.2 [M+H]+. HRESIMS (+): 626.23043 (calculated as c35H33FN3〇7 is 626.223025) ° [Example 6] (R)-3-[l-[3-[[4-(4-fluorophenoxy)phenyl) Aminoguanidino]_4_methoxyphenylmethyl]-2,4-di-side oxyimidazolidine-5-yl]propionic acid [Chem. 86] 158356.doc •80· 201212913

To a solution of the compound of Example 5 (155 mg, 0.25 mmol) in ethanol (3 mL), 10% palladium carbon (15.5 mg) was added under an argon atmosphere, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The title compound (128 mg, 96%) was obtained from the title compound (yield: 128 mg).

Melting point: 87-89 ° C IR (ATR): 3387.9, 3062.7, 1768.8, 1707.5, 1631.7, 1534.9, 1494.8, 11438.5, 1301.6, 1246.8, 1209.3, 1189.0, 1107.9, 1015.0, 942.6 cm·1. ^-NMR (DMSO-d6, 400 MHz) δ 1.83-2.00 (2H, m), 2.〇s &gt; 2.22 (2H, m), 3.86 (3H, s), 3.91 (1H, dd, J=6.1, 3.7 Hz), 4.21 (1H, d, J = 15.3 Hz), 4.46 (2H, d, J = 6.1 Hz), 4.59 (1H, d, J = 15.3 Hz), 6.95 (2H, d, J = 8.6 Hz) ), 7.00-7.07 (2H, m)} 7.11 (1H, d, J=8.6 Hz), 7.17-7.23 (2H, m), 7.33 (2H, ds J=8.6 Hz), 7.39 (1H, dd, J =8.6, 2.4 Hz), 7.66 (1H, d, J=2.4 Hz), 8.67 (1H, t, J=6.1 Hz), 11.0 (1H, s), 12·2 (1H, brs). ESIMS (+): 536.2 [M+H]+. HRESIMS (+): 536.18369 (calculated as C28H27FN307 is 536.18330) ° Elemental analysis: Actual measured value c 62.49°/. , Η 4.81 ° /. ' N 7.68 ° /. ' 158356.doc -81 - 23⁄4 201212913 Calculated for C28H26FN307 C 62.80%, 4.8 4.89%, N 7.85%. &lt;Reference Example 2&gt; 5-(2,4-dioxaxyidazolidin-1-yl)methyl-2-methoxybenzoic acid First Step 5·[(Aminylfluorenyl)amino group Indyl]-2-methoxybenzoate oxime ester [Chem. 87]

Adding glycine amine hydrochloride (5.47 g, 49.4 mmol) to a solution of 5-nonyl-2-methoxybenzoic acid (4.00 g, 20.6 mmol) in methanol (100 mL) Ethyloxyacetate (8·73 g, 41.2 mmol) was stirred and stirred at room temperature for 2.5 hours. Saturated sodium bicarbonate water/guar solution (15 〇 mL) was added to the reaction mixture, and extracted with chloroform/methanol di(7)8 〇〇〇 mLx7). The combined base layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (EtOAc: EtOAc (EtOAc:EtOAc) 〇 1645.4, 1500.5, 1432.9 IR (ATR)·· 3365.5, 3181.6, 1725.

3.76 (2H, s), 3.89 (3H, s), 3.9〇(2H, s), 5.67 (1H, brs), 158356.doc -82· 201212913 6.92-7.00 (2H, m), 7.40 (1H, dd , J=8.5} 2.4 Hz), 7.74 (1H, d, J=2_4 Hz). CIMS (+): 253.1 [M+H]+. HRCIMS (+): 253.1189 (calculated as c12H17N2〇4 is 253.1188). Second step 5-[N-(Aminocarbonyl) methoxycarbonylaminocarbonyl]_2_decyloxybenzoic acid methyl ester [Chem. 88]

Ο

MeO’

MeO was added to the compound of the first step (3.30 g, 13.1 mmol) in tetrahydro-negative β-nan solution (66 mL). Triethylamine (2 56 , 18.3 mmol), decyl chloroformate 〇 21 was added while stirring in an ice bath. mL, 15 7 mm 〇 1) and stirred under the same conditions for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with ethyl acetate (5 mL). The combined base layer was washed with brine (5 mL) and dried over anhydrous sodium sulfate. (ATR): 3373.3, 1696.1, 1676.6, 1615.2, 1480.1 cm'1 〇^-NMR (CDC13s 400 MHz) δ 3.74-3.86 (5H, m)9 3.89 (3H, s), 3.90 (3H, s), 4.52 (2H, s)} 5.50-6.10 (2H, m), 6.95 158356.doc 3 -83- 201212913 d, J=8.5 Hz), 7.30-7.48 (1H, m), 7.68 (1H, brs). CIMS (1): 311.1 [M+H]+ 〇HRCIMS (+): 311.1215 (as (: (5) 丨 must be calculated as 311.1243) 〇 third step 5-(2,4-di-side oxyimidazole pyridine-1 -yl)methyl-2-methoxybenzoic acid oxime ester [Chem. 89]

Sodium decoxide (1.31 g, 24 3 mm 〇1) was added to the second step of the compound (3 〇 1 g, 9 7 〇 mm 〇 1) in methanol, and heated to reflux for a few minutes. To the reaction mixture was added hydrazine N hydrochloric acid and extracted with ethyl acetate (50 mL EtOAc). The combined base layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The residue was purified by (4) column chromatography (EtOAc) eluted eluted elute 3052.0, 1763.4, , 1715.4, 1688.8, 1614.8, 1500.5

158356.doc -84 - 201212913 J=8.5' 2.4 Hz), 7.53 (1H, d, J = 2.4 Hz), 10.8 (1H, s). EIMS (+): 278.1 [M]+. HREIMS (+): 278.0940 (calculated as CnH&quot;]^5 is 278.0903) 〇 Fourth step 5-(2,4-di-oxyimidazolidinyl)methyl-2-methoxybenzoic acid 90]

A 2 N aqueous solution of sodium hydroxide (7 mL) was added to a MeOH solution (3 mL). The title compound (175 g, 90%) was obtained as a colorless powdery crystals.

Melting point: 214-215 ° C IR (ATR): 3056.2, 1770.8, 1690.6, 1576.8, 1463.4 cm·1. ^-NMR (DMSO-d6, 400 MHz) δ 3.79 (5H, s), 4.37 (2H 2) 7.09 (1H, d, J = 8.5 Hz), 7.39 (1H, dd, J=8.5, 1.8 Hz), 7.52 (1H,d, J=1.8 Hz), 10.8 (1H, s), 12_6 (1H, s). EIMS (+): 264.1 [M]+. HREIMS (+): 264.0739 (calculated as C12H12N2〇5 is 158356.doc -85-201212913 264.0746) 〇&lt;Reference Example 3 &gt; 3-(2,4-di-side oxyimidazole-1-yl) Methylbenzoic acid first step 3-(Aminomethyl)aminobenzyl benzoate [Chem. 91]

According to the first step of Reference Example 2, the reaction was carried out using 3-benzylsulfonyl benzyl benzoate (200 mg, 0.83 mmol) and glycine amine hydrochloride (734, 6 64 mmol) in the form of a colorless powder. The title compound 2 (198 mg, 80%) was obtained as crystals. IR (ATR): 3376.6, 3188.8, 1716.2, 1644.6, 1443.2, 1408.9 1382.1, 1270.9, 1188.5, 1098.8 cnT1. ^-NMR (CDC13s 400 MHz) δ 3.31 (3Η, s), 3.85 (2H, s), 5.37 (2H, s), 5.54 (1H, brs), 6.96 (1H, brs), 7.31-7.54 (7H, m), 7.96-8.04 (2H, m). CIMS (+): 299.1 [M+H]+. HRCIMS (+): 299.1366 (calculated as C17H19N203 is 299.1396). Second step 3-[N-(Aminomethylhydrazinyl)methoxymethylaminomethyl]benzoic acid benzyl ester 158356.doc • 86 · 201212913 [Chem. 92]

BnO

OMe NH2 was obtained according to the second step of Reference Example 2 using the compound from the first step (139 mg '0.47 mmol), methyl chloro decanoate (43.3 pL, 0.56 mmol), and obtained as a colorless oil. The title compound (170 mg, quant.). IR (ATR): 3396.7, 3205.2, 2955.3, 1703.6, 1667.2, 1472.0, 1411.9, 1276.1, 1 185.5, 1 103.1 cm-1. !H-NMR (CDCIs, 400 MHz) δ 3.79 (3H, s), 3.85 (2H, s), 4.62 (2H, s), 5.37 (3H, s), 7.31-7.50 (7H, m), 7.95 ( 1H, s), 8.01 (1H, d, J = 7.3 Hz). CIMS (+): 357.1 [M+H]+. HRCIMS (+): 357.1426 (calculated as C19H21N205 is 357.1450) ° Third Step 3-(2,4-Di-Ethyloxyimidazolidin-1-yl)-decylbenzoate (Imidification 93) 158356.doc -87- 201212913

MeO^xn4nh The title compound (107 mg, 92%) was obtained from the title compound (107 mg, EtOAc). IR (ATR): 3186.8, 3063.1, 1692.2, 1469.1, 1420.2, 1280.2, 1203.4, 1081.7, 1001.0 cm-1 ° ^-NMR (DMSO-d6, 400 MHz) δ 3.85 (5Η, s), 4.50 (2Η, s ), 7.47-7.59 (2H, m), 7.80-7.91 (2H, m), 10.9 (1H, s). EIMS (+): 248.1 [M]+. HREIMS (+): 248.0801 (calculated as C12H12N204 is 248.0797) 〇 Fourth step 3-(2,4-di- oxyimidazolidin-1-yl) decylbenzoic acid [Chem. 94]

The title compound (73.0 mg, 80%) was obtained from the title compound (yield: 73.0 mg, 80%). 158356.doc •88- 201212913 IR (ATR): 3171.1, 3055.5, 1760.6, 1696.8, 1591.4, 1459.6, 1419.2, 1300.6, 1232.0, 1183.6, 1109.0 cm·1. ^-NMR (DMSO-d6, 400 MHz) δ 3.84 (2H, s), 4.49 (2H, s), 7.44-7.55 (2H, m), 7.79-7.88 (2H, m), 10.9 (1H, s) , 13.0 (1H, s). CIMS (+): 235.1 [M+H]+. HRCIMS (+): 235.0710 (calculated as ChHhNzC^ is 235.0719). [Example 7] 5-(2,4-dioxaxyididin-1-yl)methyl-2-foxy-N-[4-(4-fluorophenoxy)phenylmethyl] Benzylamine [Chem. 95]

Triethylamine (0.32 mL, 2.28 mmol), cyanide was added to a solution of the compound of Example 2 (300 mg, 1.14 mmol) in N,N,-didecylamine (7 mL) Diethyl phosphinate (0.21 mL, 1.25 mmol) and stirred under the same conditions for 10 min, then [4-(4-fluorophenoxy)phenylindolyl]amine (248 mg, 1) • 14 mmol) of N,N,-dimethylformamide solution (3 mL) and stirred under the same conditions for 30 min. Water was added to the reaction mixture and extracted with chloroform / methanol = 10/1 (20 mL x 3). The combined base layer was washed with saturated brine (5 〇 158356.doc -89 - 201212913 mL), and dried over anhydrous sodium sulfate to concentrate the reaction mixture. After the residue was purified by hydrazine column chromatography (Si60N, ethyl acetate), it was recrystallized (hexane: ethyl acetate = 1:1), and obtained as a colorless powdery crystal. The title compound (491 mg, 93%).

Melting point: 140-141 ° C IR (ATR): 3380.0, 3062.1, 1718.6, 1633.6, 1535 5 1498.3 cm'1 ° !H-NMR (DMSO-d6, 400 MHz) δ 3.79 (2H, s)j 3 87 (3H, s), 4.39 (2H, s), 4.46 (2H, d, J=6.1 Hz), 6.95 (2H, d, J=8.5

Hz), 6.98-7.07 (2H, m), 7_12 (1H, d, J = 8.5 hz) 7.15-7.25 (2H, m), 7.33 (2H, d, J = 8.5 Hz), 7.36 (1H, dd, j = 8.5, 2.4 Hz), 7'62 (1H, d, J = 2.4 Hz), 8.69 (1H, t' j =: 6" Hz), 10.9 (1H, s). ESIMS (+): 464.2 [M+H]+ 〇 HRESIMS (+): 464.16260 (calculated as C25H23FN3〇5 is 464.16217). Elemental analysis: Actual measured value C 64.72%, Η 4.84%, N 9 〇 5%, calculated as C25H22FN305 C 64.79%, 4.7 4.78%, N 9 Q7%. &lt;Reference Example 4&gt; 4·[4·(Aminomethyl)phenoxy]-N,N-dimethylaniline First step 4-[4-(didecylamino)phenoxy]benzene Nitrile [Chem. 96] 158356.doc •90· 201212913

Add 37% formalin aqueous solution (3.86 mL) to 4-(4-aminophenoxy)benzonitrile (1.00 g, 4.76 mmol) in methanol (9·5 mL) with ice-cooling and stirring. , 47.6 mmol), acetic acid (0.82 mL, 14.3 mmol), cyano-sodium hydride (897 mg, 14.3 mmol) and stirred at room temperature for 1 hour. The title compound (1.15 g, quant.) was obtained as a colorless powdery crystals. IR (ATR): 2893.9, 2223.4, 1599.1, 1514.9, 1492.6, 1350.7, 1252.5 cm·1. !H-NMR (CDC13, 400 MHz) δ 2.98 (6H, s), 6.73-6.79 (2H, m), 6.93-7.01 (4H, m), 7.54-7.59 (2H, m). EIMS (+): 238 [M]+. HREIMS (+): 238.1116 (calculated as C15H14N20 is 238.1106). Second step 4-[4-(Aminomethyl)phenoxy]-N,N-dimethylaniline [Chem. 97]

Add lithium aluminum halide (2.61 g, 68.8 158356.doc -91 - 201212913 mmol) in a solution of the first step of the compound (8.20 g, 34.4 mmol) in tetrahydrofuran (98 mL) with ice-cooling and stirring. And stirring at room temperature for 3 〇 minutes β added to the reaction mixture of water (2.61 mL), 15% aqueous sodium hydroxide 61 'bu water (7 83 melon and stirred for 6 hours) the reaction mixture was 7 vine soil (four) and The title compound (8 29 g, 99%) was obtained as crystals of crystals of crystals of crystals. NMR (CDC13, 400 MHz) δ 1.50 (2Η, brs), 2.93 (6H, s), 3.81 (2H, s), 6.73 (2H, dt, J=6.4, 3.9 Hz), 6.90 (2H, dt, J =5.7, 3.3 Hz), 6.95 (2H, dd, J=6.7, 2.4 Hz), 7.21 (2H, d, J=8.6 Hz) 〇EIMS (+): 242 [M]+ 〇HREIMS(1):242”396( The calculated value as cwwo is 242.1419) 〇 &lt;Reference Example 5&gt; 4-[4-(Aminomethyl)phenoxy]benzoate ethyl ester hydrochloride [Chem. 98] 0

Concentrated hydrochloric acid (2.76 mL) was added to a solution of ethyl 4-(4-cyanophenoxy)benzoate (5.91 g, 22.1 mmol) in methanol (63 mL), and 10% palladium hydroxide was added under argon. Carbon (591 mg) was stirred at room temperature for 10 hours under a hydrogen atmosphere. After the insoluble matter of the reaction mixture was filtered off with celite, the filtrate was evaporated to dryness, and the residue was evaporated to dryness to afford crystals of 158356.doc -92 - 201212913 title compound (6.02 g, 89%) ). IR (ATR): 2965.1, 1715.6, 1599.5, 1499.8, 1277.0, 1250.5, 1161.8, 1096.3, 1012.9 cm·1. 'H-NMR (DMSO-d6, 400 MHz) δ 1.29 (3H, t, J=7.0 Hz), 4.01 (2H, s), 4.28 (2H, q, J=7.1 Hz), 7.04 (2H, d, 1 = 8.5 Hz), 7.16 (2H, d, J = 8.5 Hz), 7.58 (2H, d, J = 8.5 Hz), 7.97 (2H, d, J = 8.5 Hz), 8.53 (3H, brs). EIMS (+): 271 [M]+. HREIMS (+): 271.1192 (calculated as C丨6H丨7N〇3 is 271.1208). &lt;Examples 8 to 21&gt; According to the method of Example 7, the compound of Reference Example 2 or Reference Example 3 and the corresponding amine were used to carry out the reaction, and the compound of Table 3 was obtained. [9%

Example number ring BY V1 V2 nz 8 4-F-Ph 0 CH CH 1 H 9 4-F-Ph 0 CH CH 0 H 10 4-F-Ph 0 CH CH 0 2-MeO 11 Ph 0 CH CH 1 2 -MeO 12 4-Me-Ph 0 CH CH 1 2-MeO 13 4-NC-Ph 0 CH CH 1 2-MeO 14 4-Me2N-Ph 0 CH CH 1 2-MeO 15 4-MeO-Ph 0 CH CH 1 2-MeO 16 N-Boc-piperidin-4-yl 0 CH CH 1 2-MeO 17 4-F-Ph S CH CH 1 2-MeO 158356.doc -93· 201212913

18 4-F-Ph 0 N CH 1 2-MeO 19 4-F-Ph 0 CH N 1 2-MeO 20 4-EtOOC-Ph 0 CH CH 1 2-MeO 21 cyclohexyl 0 CH CH 1 2-MeO

[Embodiment 8]

3-(2,4-Di-oxyimidazolidine-1-yl)indolyl-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide as a colorless powdery crystal melting point: 193-195 ° C IR (ATR): 3302.0, 2953.4, 2732.1, 1756.7, 1719.7, 1632.6, 1543.4, 1494.4, 1458.9, 1348.0, 1311.8, 1250.3, 1211.2, 1188.0, 1115.2 cm·1. *H-NMR (DMSO-d6, 400 MHz) δ 3.85 (2H, s), 4.45 (2H, d, J = 6.1 Hz), 4.48 (2H, s), 6.94 (2H, d9 J=8.5 Hz), 6.98-7.06 (2H, m), 7.20 (2H, t, J=8.8 Hz), 7.32 (2H, d, J=7.9 Hz), 7.40-7.49 (2H, m), 7.75 (1H, s), 7.80 (1H, d, 3 = 6.7 Hz), 9.05 (1H, t, J = 6.1 Hz), 10.9 (1H, s). ESIMS (-): 432.1 [M-H]+. HRESIMS (-): 432.13579 (calculated as C24H19FN304 is 432.13596). [Embodiment 9]

3-(2,4-Di-oxyimidazolidine-1-yl)indolyl-N-[4-(4-fluorophenoxy)phenyl]benzamide A colorless powdery crystal melting point: 224- 226 ° C IR (ATR): 3265.1, 3049.7, 1761.5, 1708.3, 1649.5, 1528.6, 158356.doc •94· 201212913 1496.6, 1466.0, 1407.2, 1320.2, 1211.0, 1098.9, 1011.6 cm'1 〇^-NMR (DMSO- D6, 400 MHz) δ 3.88 (2H, s), 4.52 (2H, s), 6.98-7.07 (4H, m), 7.21 (2H, t, J=8.8 Hz), 7.45-7.54 (2H, m), 7.75 (2H, d, J=9.1 Hz), 7.80 (1H, s), 7.86 (1H, d, J=7.3 Hz), 10.3 (1H, s), 10_9 (1H, s). ESIMS (-): 418, 1 [M-H]+. HRESIMS (-): 418.12037 (calculated as C23H17FN304 is 418.12031). [Embodiment 10]

5-(2,4-Di-oxyimidazolidine-1-yl)indol-2-yloxy-&gt;1-[4-(4-fluorophenoxy)phenyl]benzamide is colorless Powder crystal melting point: 202-204 ° C IR (ATR): 3346.4, 3179.3, 3070.9, 1770.2, 1712.8, 1638.0, 1537.5, 1496.7, 1468.4, 1425.1, 1320.4, 1248.5, 1209.1, 1097.3, 1021.6, 935.2, 873.4, 828.1, 746.7, 710.0, 621.2, 514.6, 487.6, 416.1 cnT1 ° ^-NMR (DMSO-d6, 400 MHz) δ 3.82 (2H, s), 3.88 (3H, s), 4.41 (2H, s), 6.96- 7.05 (4H, m), 7.13-7.24 (3H, m), 7.39 (1H, dd, J=8.6, 1.8 Hz), 7.51 (1H, d, J=1.8 Hz), 7.72 (2H, d, J= 8.6 Hz), 10.1 (1H, s), 10.9 (1H, s). ESIMS (+): 450.1 [M+H]+. HRESIMS (+): 450.14709 (calculated as C24H21FN305 is 450.14652) ° •oaf 158356.doc -95- 201212913 [Example 11]

5-(2,4-di-oxyimidazolidine-1-yl)methyl-2-decyloxy-N-(4-phenoxyphenylmethyl)benzamide amide colorless powdery crystal melting point : 115-117 ° C IR (ATR): 3334.9, 3142.0, 3061.9, 1770.6, 1711.4, 1622.6, 1539.7, 1488.5, 1425.2, 1315.9, 1230.6, 1164.0, 1097.4, 1023.0, 951.9, 870.5, 815.0, 761.9, 691.8, 637.8 , 595.2, 512.7, 416.2 cm-1. !H-NMR (DMSO-d6, 400 MHz) δ 3.79 (2H, s), 3.87 (3H, s), 4.39 (2H, s), 4.47 (2H, d, J=6.1 Hz), 6.95-7.00 ( 4H, m), 7.07-7.15 (2H, m), 7.32-7.40 (5H, m), 7.63 (1H, d, J=2.4 Hz), 8.70 (1H, t, J=6.1 Hz), 10.9 (1H , s). ESIMS (+): 446.2 [M+H]+. HRESIMS (+): 446.17172 (calculated as C25H24N3〇5 is 446.17160). [Embodiment 12]

5-(2,4-di- oxyimidazolidine-1-yl)indol-2-yloxy-N-[4-(4-triyloxy)phenylindenyl]benzamide is colorless Powdered crystal melting point: 122-124 ° C IR (ATR): 3586.8, 3380.6, 3166.3, 3063.0, 2921.0, 2731.7, 1765.7, 1708.5, 1645.8, 1545.9, 1497.9, 1464.3, 1430.2, 1342.3, 1302.7, 1234.6, 1167.8, 1102.4,1010.0,946.2, 158356.doc •96- 201212913 876.9, 809.9, 753.1, 690.7, 606.8, 498.0 cm·1 ° !H-NMR (DMSO-d6, 400 MHz) δ 2.27 (3H, s), 3.79 ( 2H, s), 3.86 (3H, s), 4.39 (2H, s), 4.45 (2H, d, J=6.1 Hz), 6.88 (2H, d, J=8.6 Hz), 6_93 (2H, d, J =9.2 Hz), 7.12 (1H,d,J=8.6 Hz), 7.16 (2H, d, J=7.9 Hz), 7.31 (2H, d, J=8.6 Hz), 7.36 (1H, dd, J=8.6 , 2.4 Hz), 7.62 (1H, d, J=2.4 Hz), 8.69 (1H, t, J=6.1 Hz), 10.9 (1H, s). ESIMS (+): 460.2 [M+H]+. HRESIMS (+): 460.18656 (calculated as C26H26N305 is 460.18725) ° [Example 13]

5-(2,4-di- oxyimidazolidine-1-yl)methyl-2-decyloxy-N-[4-(4-cyanophenoxy)phenylf-yl]benzamide Colorless powdery crystalline melting point: 182-184 ° C IR (ATR): 3371.0, 3058.2, 2226.2, 1770.1, 1691.7, 1648.1, 1528.3, 1497.2, 1416.8, 1287.0, 1255.3, 1167.7, 1121.9, 1012.8, 953.0, 876.4, 851.1 , δ δ δ δ δ δ δ , 4.50 (2H, d, J=6.1 Hz), 7.03-7.15 (5H, m), 7.34-7.44 (3H, m), 7.63 (1H, d, J=2.4 Hz), 7.81 (2H, d, J =9.2 Hz), 8·75 (1H, t, J=6.1 Hz), 10.9 (1H, s). ESIMS (+): 471.2 [M+H]+. 158356.doc -97- 201212913 HRESIMS (+): 471.16622 (calculated as C26H23N405 is 471.16684). [Embodiment 14]

5-(2,4-Di-oxyimidazolidine-1-yl)methyl-2-methoxy-N-[4-[4-(didecylamino)phenoxy]phenylmethyl Benzoguanamine light yellow powdery crystalline melting point: 139-140 ° C IR (ATR): 3347.0, 3146.1, 2937.9, 1770.1, 1709.9, 1622.5, 1499.3, 1468.4, 1422.6, 1314.4, 1228.1, 1161.8, 1097.3, 1023.8 , 947.8, 872.0, 815.7, 762.1, 685.6, 635.9, 596.4, 501.3, 416.0 cm·1 ° !H-NMR (DMSO-de, 400 MHz) δ 2.85 (6H, s), 3.78 (2H, s), 3.86 (3H, s), 4.38 (2H, s), 4.42 (2H, d, J=5.5 Hz), 6.74 (2H, d, J=9.2 Hz), 6.84 (2H, d, J=8.6 Hz), 6.89 (2H, d, J=9.2 Hz), 7.11 (1H, d, J=9.2 Hz), 7.26 (2H, d, J=8.6 Hz), 7.36 (1H, dd, J=8.6, 2.4 Hz), 7.61 (1H, d, J = 2.4 Hz), 8.65 (1H, t, J = 5.5 Hz), 10.9 (1H, s). ESIMS (+): 489.2 [M+H]+. HRESIMS (+): 489.21409 (calculated as C27H29N405 calculated as 489.21379) ° Elemental analysis: Actual measured value C 66.32% ' H 5.87%, N 11.27% ' Calculated as C27H28N405 C 66.3 8%, 5.7 5.78%, N 11.47% . [Example 15] 5-(2,4-di- oxyimidazolidine-1-yl)methyl-2-oxime--[-(4-oxo 158356.doc -98- 201212913

Phenyloxy)phenylindenyl]benzamide A colorless powdery crystalline melting point: 139-140 ° C IR (ATR): 3352.9, 3 140.4, 2942.7, 2837.3, 1770.0, 1709.8, 1624.5, 1536.9, 1498.0, 1470.0, 1426.2, 1311.7, 1224.2, 1163.8, 1098.2, 1024.5, 953.7, 875.6, 840.7, 762.4, 684.2, 636.0, 596.8, 504.0, 417.3 cm-1 ° ^-NMR (DMSO-d6, 400 MHz) δ 3.73 (3H , s), 3.78 (2H, s), 3.86 (3H, s), 4.38 (2H, s), 4.44 (2H, d, J=6.1 Hz), 6.88 (2H, d, J=8.6 Hz), 6.92 -6.99 (4H, m), 7.11 (1H, d, J=8.6 Hz), 7.29 (2H, d, J=8.6 Hz), 7.36 (1H, dd, J=8.6, 2.4 Hz), 7.62 (1H, d, J = 2.4 Hz), 8.67 (1H, t, J = 6.1 Hz), 10.9 (1H, s). ESIMS (+): 476.2 [M+H]+. HRESIMS (+): 476.18309 (calculated as C26H26N3〇6 is 476.18216) ° Elemental analysis: Actual measured value C 65.83%, H 5.35%, N 8.94°/. As C26H26N306 calculated value C 65.67%, Η 5.30%, N 8.84%. [Example 16] 5-(2,4-Di-side oxyimidazolidin-1-yl)indol-2-yloxy-N-[4-(4-t-butoxycarbonylpiperidine-1 -ethyloxy)phenylindolyl]benzamine white solid IR (ATR): 3395.6, 3121.7, 2946.2, 1763.7, 1712.4, 1693.9, 1634.6, 1597.8, 1510.1 cm-1 ° !H-NMR (DMSO-d6 , 400 MHz) δ 1.39 (9Η, s), 1.44-1.52 158356.doc -99- 201212913 (2H, m), 1.84-1.89 (2H, m), 3.16 (2H, s), 3.60-3.66 (2H, m), 3.78 (2H, s), 3.86 (3H, s), 4.38-4.41 (4H, m), 4.48-4.52 (1H, m), 6.92 (2H, d, J=8.5 Hz), 7.11 (1H , d, J=8.7 Hz), 7.23 (2H, d, J=8.5 Hz), 7.36 (1H, dd, J=2.4, 8.7 Hz), 7.61 (1H, d, J=2.4 Hz), 8.62 (1H , t, J = 6.1 Hz), 10.85 (1H, s). ESIMS (+): 553.3 [M+H]+ 〇HRESIMS (+): 553.26644 (calculated as C29H37N407 is 553.26622) ° Elemental analysis: Actual measured value C 62.62%, 6.5 6.55%, N 10.10%, as C29H36N407. The calculated value of 0.2H2O is 63.03%, Η 6.57%, and N 10.14%. [Example 17]

5-(2,4-di- oxyimidazolidine-1-yl)indolyl-2-methoxy-1^-[4-(4-fluorophenylthio)phenylmethyl]phenylamine Colorless powdery crystalline melting point: 149-150 ° C IR (ATR): 3142, 1710, 1625, 1544, 1467, 1422, 1252, 1222, 1098, 1029, 815, 627, 416 cm·1. !H-NMR (CDC13, 400 MHz): δ 3.78 (2H, s), 3.94 (3H, s), 4.52 (2H, s), 4.64 (2H, d, J=6.1 Hz), 6.90-7.05 (3H , m), 7.24-7.27 (4H, m), 7.32-7.43 (3H, m), 7.68 (1H, br), 8.12 (1H, d, J=2.4 Hz), 8.19 (1H,t, J=5.5 Hz). ESIMS (+): 480 [M+H]+. HRESIMS (+): 480.1392 (calculated as C25H23FN304S 158356.doc -100- 201212913 480.1393). [Example 18] 5-(2,4-di- oxyimidazolidine-1-yl)methyl-2-decyloxy-N-[[6-(4-fluorophenoxy)-pyridyl- Colorless powdered crystalline IR (ATR): 3591, 3398, 3162, 3070, 1765, 1712, 1642, 1537, 1505 cm '1 ° ^-NMR (CDC13, 400 MHz) : δ 3.78 (2Η, s), 3.95 (3H, s), 4.53 (2H, s), 4.62 (2H, d, J=6.1 Hz), 6.89 (1H, d, J=8.5

Hz), 7.00 (1H, d, J=8.5 Hz), 7.07-7.09 (4H, m), 7.40 (1H, brs), 7.42 (1H, dd, J=8.5, 2.4 Hz), 7.75 (1H, dd , J=8.5, 2.4

Hz), 8.12 (2H, d, J=2.4 Hz), 8.15 (1H, d, J=2.4 Hz), 8.21 (1H, t, J=6.1 Hz). ESIMS (+): 465.2 [M+H]+. HRESIMS (+): 465.15781 (calculated as C24H22FN405 465.15742) ° [Example 19] 5-(2,4-di- oxy-imidazolidine-1-yl)methyl-2-methoxy-N- [[5-(4-Fluorophenyl-oxy)pyridin-2-yl]indolyl]benzamide. Colorless powdery crystalline IR (ATR): 3571, 3517, 3125, 3054, 2734, 1762, 1708, 1625, 1532 cm·1. !H-NMR (CDCI3, 400 MHz): δ 3.78 (2Η, s), 4.01 (3H, s), 4.53 (2H, s), 4.77 (2H, d, J=5.4 Hz), 6.98-7.08 (5H } m), 158356.doc -101 - 201212913 7.25 (1H, dd, J=8.5, 2.4 Hz), 7.34 (1H, d, J=8.5 Hz), 7.40 (1H, brs), 7.41 (1H, dd, J = 8.5, 2.4 Hz), 8.13 (1H, d, J = 2.4 Hz), 8.33 (1H, d, J = 2.4 Hz), 8_90 (1H, t, J = 5.4 Hz). ESIMS (+): 465.2 [M+H]+. HRESIMS (+): 465.15784 (calculated as C24H22FN405 is 465.15742) ° [Example 20] 4-[4-[[5-[(2,4-di-[i-[pi] Ethyl-2-phenyloxybenzamine] decyl]phenoxy]benzoic acid ethyl ester colorless powdery crystalline IR (ATR): 3335.0, 3 137.7, 3065.9, 1769.9, 1710.3, 1598.9, 1499.3, 1469.1, 1425.1, 1308.7, 1279.0, 1246.5, 1163.5, 1098.3, 1015.2, 952.5, 874.4, 843.8, 764.1, 638.5, 596.2, 498.4, 417.1 cm_1. !H-NMR (CDC13, 400 MHz) δ 1.38 (3Η, t, J=7.3 Hz), 3.79 (2H, s), 3.97 (3H, s), 4.36 (2H, q, J=7.3 Hz), 4.54 (2H, s), 4.69 (2H, d, J=5.5 Hz), 6.95-7.07 (5H, m)5 7.37 (2H, d, J=8.6 Hz), 7.42 (1H, dd, J=8.6, 2.4 Hz), 7.73 (1H, brs), 8.01 (2H, d, J=9.2 Hz), 8.15 (1H, d, J=2.4 Hz), 8.24 (1H, t, J=5.5 Hz). ESIMS (+): 518.2 [M+H]+. HRESIMS (+): 518.19243 (calculated as C28H28N307 is 518.19272). [Example 21] 158356.doc •102-201212913 5-(2,4-Di-side oxyimidazolidine-1-yl)methyl-2-decyloxy-N-[4-(cyclohexyloxy) Phenylfluorenyl]benzamine white solid IR (ATR): 3341.5, 3121.5, 2932.2, 2856.4, 1796.4, 1710.4, 1623.0, 1546.4 cm-1 ° !H-NMR (DMSO-d6, 400 MHz) δ 1.25- 1.40 (5Η, m), 1.49-1.54 (1Η, m), 1.66-1.70 (2H, m), 1.87-1.90 (2H, m), 3.31 (3H, m), 3.78 (2H, s), 3.86 ( 3H, s), 4.25-4.30 (1H, m), 4.38-4.40 (4H, m), 6.87 (2H, d, J=8.8 Hz), 7.11 (1H, d, J=8.5 Hz), 7.21 (2H , d, J=8.8 Hz), 7.36 (1H, dd, J=2.4, 8.5 Hz), 7·61 (1H, d, J=2.4 Hz), 8·60 (1H, t, J=6.1 Hz) , 10.85 (1H, s). ESIMS (+): 452.2 [M+H]+. HRESIMS (+): 452.21918 (calculated as C25H3〇N305 is 452.21855) ° Elemental analysis: Actual measured value C 66.34%, H 6.44%, N 9.29%, calculated as C25H29N305 C 66.50%, 6.4 6.47%, N 9.31 %. [Example 22] 5-(2,4-di-oxo-3-butylimidazolidinyl-p-yl)methyl-2-methoxy-N-[4-(4-fluorophenoxy)benzene Benzohydrazide [100]

158356.doc -103- 201212913 Adding carbonic acid (135 mg, 〇·98 mmol) to the ν, hydrazine-dimercaptoamine solution (6.5 mL) of the compound of Example 7 (300 mg '0.65 mmol), Iobutane (88.8 pL '0.78 mmol) was stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate (3 〇 mL x 3). The combined base layer was washed with saturated brine (3 mL) and dried over anhydrous sodium sulfate. The title compound (330 mg, 97%) was obtained from crystals eluted elution elution elution elution elution elution elution elution

Melting point: 37-38 ° C IR (ATR): 3397.2, 2934.4, 1768.1, 1702.3, 1649.1, 1494.2, 1461.3, 1245.3, 1209.1 cm'1 〇1H-NMR (CDCl3, 400 MHz) S0.94 (3H, t , J=7.3Hz), 1.28- 1.40 (2H, m), 1.56-1.66 (2H, m), 3.52 (2H, t, J=7.3

Hz), (2H, s), 3.94 (3H, s), 4.55 (2H, s), 4.64 (2H, d, J=5.5 Hz), 6.91-7.06 (7H, m), 7.32 (2H, d, J=8.6 Hz), 7.38 (1H, dd, J=8.6, 2.4 Hz), 8.13 (1H, d, J=2.4 Hz), 8.17 (1H, t, J=5.5 Hz) o ESIMS (+): 520.2 [M+H]+. HRESIMS (+): 520.22438 (calculated as C29h3iFN3〇5 is 520.22477) ° Elemental analysis: Actual measured value C 66.91%, H 6.05%, N 8.06%, calculated as C29H3〇FN305 C 67.09%, η 5.82%, N 8.09%. [Example 23] 104·158356.doc 201212913 5-(2,4-Di-oxo-3-(2-benzyloxyethyl)imidazol-1-yl)indenyl-2-methoxy- N-[4-(4-fluorophenoxy)phenylmethyl]benzamide [Chem. 101]

The title compound (150 mg, 0.32 mmol) and the benzyl 2-bromoethyl ether (75.9 gL, 0.48 mmol) were reacted according to Example 22 to give the title crystals Compound (180 mg, 94%) 〇IR (ATR): 3408.2, 2948.6, 1761.5, 1698.3, 1644.6, 1608.3, 1527.7, 1496.4, 1469.7, 1447.8, 1358.8, 1299.7, 1247.5, 1211.5 cm·1. !H-NMR (CDC13, 400 MHz) δ 3.67-3.73 (4Η, m), 3.78 (2H, t, J=5.5 Hz), 3.92 (3H, s), 4.54 (4H, s), 4.64 (2H, d, J = 5.5 Hz), 6.89-7.06 (7H, m), 7.25-7.38 (8H, m), 8.13 (1H, d, J = 2.4 Hz), 8.17 (1H, t, J = 5.5 Hz). ESIMS (+): 598.2 [M+H]+. HRESIMS (+): 598.23497 (calculated as C34H33FN306 is 598.23534). [Example 24] 5-(2,4-di-oxo-3-(2-carbolinylethyl)imidazolidinyl)-methyl-2-indenyloxy_N_[4-(4 -fluorophenoxy)phenylindolyl]benzamide [Chem. 102] 158356.doc • 105- 201212913

Add potassium carbonate (174 mg, I.% mm〇1), small (2) to the compound of Example 7 (193 mg, 0.42 mmol) and Ν·-dimethylamine amine solution (4 mL). - Murine ethyl) tartrate hydrochloride (117 mg, 0.63 mmol) and stirred at 80 ° C for 1 hour. Water was added to the reaction mixture and extracted with ethyl acetate (15 mL×3). The combined base layer was washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography ( EtOAc EtOAc EtOAc EtOAc EtOAc

Melting point: 37-38 ° C IR (ATR): 3397.6, 2948.4, 1767.8, 1704.2, 1650.3, 1609.4, 1528.0, 1495.0, 1462.7, 1424.2, 1357.6, 1297.3, 1246.3, 1209.7 cm-1. !H-NMR (CDC13, 400 MHz) δ 2.50 (4H, brs), 2.59 (2H, t, J=6.4 Hz), 3.62-3.70 (6H, m), 3.72 (2H, s), 3.94 (3H, s), 4.56 (2H, s), 4.64 (2H, d, J=5.5 Hz), 6.91-7.06 (6H, m), 7.32 (2H, d, J=8.6 Hz), 7.39 (1H, dd, J =8.6, 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz), 8.18 (1H, t, J = 5.5 Hz). ESIMS (+): 577.2 [M+H]+. HRESIMS (+): 577.24601 (calculated as C3lH34FN4〇6 is 577.24624) ° 158356.doc -106- 201212913 Elemental analysis: Actual measured value C 66.91%, Η 6.05%, N 8.06%, calculated as C29H3〇FN305 C 67.09%, Η 5.82%, N 8.09%. [Example 25] 5-(2,4-di-oxy-3-cyclopropylimidazolidin-1-yl)methyl-2-methoxy-N-•[4-(4-fluorophenoxy) Phenylmethyl]benzamide [化103]

Add cyclopropyl benzyl acid (92.8 mg, 1.08 mmol), sodium carbonate (114 mg, 1.08 mmol) to a solution of the compound of Example 7 (250 mg, 0.54 mmol) in 1,2-dichloroethane (5 mL). ), copper acetate (98.1 mg, 0.54 mmol), 2,2'-linked ratio '^(84·3 mg, 0.54 mmol), and mixed at 70 ° C for 3 hours. A saturated aqueous solution of ammonium chloride was added to the mixture and the mixture was applied to ethyl acetate (20 mL×3). The combined layers were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The title compound (206 mg, 76%) was obtained.

Melting point: 50-52 ° C IR (ATR): 3395.3, 2933.5, 1769.2, 1708.1, 1649.0, 1528.1, 1494.7, 1459.1, 1359.7, 1299.6, 1244.9, 1209.0, 1188.4 cm'1 °

S 158356.doc •107- 201212913 ^-NMR (CDC13, 400 MHz) δ 0.92-1.00 (4H, m), 2.57-2.65 (1H, m), 3.65 (2H, s), 3.94 (3H, s), 4.53 (2H, s), 4.64 (2H, d, J=5.5 Hz), 6.91-7.06 (7H, m), 7.32 (2H, d, J=8.6 Hz), 7.39 (1H, dd, J-8.6, 2.4 Hz), 8.12 (1H, d, J=2.4 Hz), 8.18 (1H, t, J=5.5 Hz). ESIMS (+): 504.2 [M+H]+. HRESIMS (+): 504.19423 (calculated as c28h27FN3〇5 is 504.19347). Elemental analysis: Actual measured value C 66.91%, Η 6.05%, N 8.06%, calculated as C29H3 〇FN305 C 67.09%, Η 5.82%, N 8.09%. [Example 26] 5-(2,4-di-oxo-3-(2-hydroxyethyl)imidazolidinyl)-indenyl-2-yloxy-N-[4_(4-fluorobenzene) Oxy)phenyl phenyl]benzamide [化104]

Add 10% palladium on carbon (15.9 Mg) to argon under the argon atmosphere of the compound of Example 23 (159 mg '0,27 mmol) in methanol/tetrahydro hydrazine = 1/1 solution (3 mL). Stir at room temperature for 丨丨 hours. After the insoluble matter of the reaction liquid was filtered off with diatomaceous earth, the filtrate was evaporated under reduced pressure, and the residue was purified by a gel column chromatography (Biotarge; SNAP Cartridge KP-Sil; ethyl acetate: methanol). Ο 158356.doc -108· 201212913 The title compound (132 mg, 96%) was obtained.

Melting point: 101-102 ° C IR (ATR): 3383.2, 2933.1, 1757.3, 1693.8, 1645.8, 1606.1, 1526.0, 1495.9, 1460.5, 1416.1, 1389.4, 1296.1, 1246.3, 1209.8, 1184.9 cm·1 ° ^-NMR ( CDCls, 400 MHz) δ 2.80 (1H, t, J=5.8 Hz), 3.73-3.80 (4H, m), 3.81-3.88 (2H, m), 3.95 (3H, s), 4·57 (2H, s ), 4.64 (2H, d, J=5.5 Hz), 6.91-7.06 (7H, m), 7.31 (2H, d, J=8.6 Hz), 7.39 (1H, dd, J=8.6, 2.4 Hz), 8.11 (1H, d, J = 2.4 Hz), 8.19 (1H, t, J = 5.5 Hz). ESIMS (+): 508.2 [M+H]+. HRESIMS (+): 508.18835 (calculated as C27H27FN306 is 508.18839) ° Elemental analysis: Actual measured value C 63.79%, H 5.30%, N 8.23%, calculated as C27H26FN306 C 63.90%, Η 5.16%, N 8.28%. [Example 27] 4-[4-[5-(2,4-di- oxy-3-phospho-p-m.sodium-l-yl)decyl-2-methoxybenzoquinone Ethyl]phenoxy]benzoic acid ethyl ester [Chem. 105]

EtOOC

环 Add cyclopropyl leucovorin (395 mg, to the compound of Example 20 (1.19 g, 2.30 mmol) of 1,2-dichloroethylene &lt;1^158356.doc -109-201212913 in a burning solution (11.5 mL). 4.60 mm 〇ι), sodium carbonate (488 mg, 4.60 mmol), copper acetate (418 mg, 2 3 〇 mmol), 2,2'-linked ratio (359 mg, 2.3 0 mmol) at 70 ° C The next drop is 6 hours. A saturated aqueous solution of chlorinated chloride was added to the reaction mixture and extracted with ethyl acetate (30 mL x 3). The combined layers were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The title compound (517 mg, 40%) was obtained as a colorless powdery crystals eluted from EtOAc (EtOAc) ). IR (ATR): 3395.2, 2981.0, 1769.3, 1704.9, 1650.0, 1597.4, 1497.7, 1460.5, 1430.7, 1365.4, 1274.7, 1235.0, 1161.1, 1098.8, 1015.2, 947.8, 871.8, 821.1, 749.8, 648.4, 595.1, 501.6, 43 5.5 cm-1 ° !H-NMR (CDC13, 400 MHz) δ 0.93-1.00 (4H, m), 1.38 (3H, t, J=7.3 Hz), 2.57-2.65 (1H, m), 3.65 (2H, s), 3.96 (3H, s), 4.36 (2H, q, J=7.3 Hz), 4.53 (2H, s), 4.68 (2H, d, J=5.4

Hz), 6.95-7.01 (3H, m), 7.03 (2H, d, J=8.5 Hz), 7.35-7.43 (3H, m), 7.97-8.03 (2H, m), 8.13 (ih,d,J= 2.4 Hz), 8.22 (1H, t, J = 5.4 Hz). ESIMS (+): 558.2 [M+H]+. HRESIMS (+): 558.22357 (calculated as C3iH32N3〇7 is 558.22402) 〇 [Example 28] 158356.doc •110- 201212913 4-[4-[5-(2,4-Di-Alkoxy-3- Cyclopropyl miso-1 -yl)methyl 2 -nonyl phenyl hydrazino fluorenyl] phenoxy] benzoic acid [Chem. 106]

A solution of the compound of Example 27 (483 mg, 0.87 mmol) in ethanol (2 mL) was evaporated. After adding 1 N hydrochloric acid to the reaction mixture to make pH = 3, extraction with ethyl acetate (30 mL x 3). The combined base layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (Bi〇targe; SNAP Cartridge KP-Sil; ethyl acetate: decyl alcohol).

The title compound (28 mg, 61%) was obtained as crystals crystals. Melting point: 77-79 ° C IR (ATR): 3383.5, 2928.0, 1768.7, 1705.4, 1596.3, 1498.1, 1429.4, 1304.2, 1233.1, 1158.5, 1 1 10.1, 1015.0, 945.8, 874.1, 819.9, 772.1, 750.0, 596.0 , 499.5, 438.1 cm*1 〇! H-NMR (DMSO-d65 400 MHz) δ 0.78-0.84 (4H, m)5 2.48-2.56 (1H, m), 3.73 (2H, s), 3.87 (3H, s ), 4.41 (2H, s), 4.5〇(2H, d, J=5.5 Hz), 6.99 (2H, d, J=8.6 Hz), 7.06-7.15 (3H, m), 7.35-7.43 (3H, m ), 7.64 (1H, d, J=2.4 Hz), 7.92 (2H, d, J=8.6 Hz), 8.74 (1H, t, J=5.5 Hz), 12.8 (1H, brs). EIMS (+): 530.2 [M]+ 〇 β 158356.doc -Ill - 201212913 HREIMS (+): 530.19283 (^ ^ C29H28N3〇7 tf # ^ 530.19272). [Example 29] 4-[4-[5-(2,4-one-oxyimidazolidinyl)methyl-2-methoxybenzoguanamine fluorenyl]phenoxy] benzoic acid [Chemical 107] ]

Add 1 N aqueous sodium hydroxide solution (2.38 mL) to a solution of the compound of Example 20 (615 mg, 1 _ 19 mmol) in ethanol (4 mL) and heat to room temperature for 3 hours, then at 80 ° Heat and stir for 4 hours at °C. After adding 1 N hydrochloric acid to the reaction mixture to make pH=3, the precipitated crystals were taken, and the residue was purified by a gel column chromatography (Biotarge; SNAP Cartridge KP-Sil; chloroform:methanol). The title compound (355 mg, 61 ° / 〇) was obtained as colorless crystals.

Melting point: 120-122 ° C IR (ATR): 3386.7, 3059.6, 1764.2, 1705.7, 1636.6, 1596.4, 1535.0, 1498.3, 1462.2, 1415.7, 1305.8, 1231.1, 1159.7, 1103.0, 1015.1, 953.1, 846.6, 816.4, 750.2 , 692.0, 631.5, 597.0, 500.1, 415.4 cm-1. </ RTI> <RTIgt; , J=9.2 158356.doc •112- 201212913

Hz), 7.08 (2H, d, 1=8.6 Hz), 7.l2 (1H, d, J=8.6 Hz), 7.35-7.43 (3H,m), 7.64 (1H,d,J=2.4 Hz), 7 92 (2h,d,j=9 2 Hz), 8.75 (1H,t,J=6.1 Hz), 10.9 〇H, s), 12 8 (ih, (iv). EIMS (+): 490.2 [M]+ HREIMS (+): 490 16167 (calculated as C26H24N3〇7 is 490.16142). [Example 30] 4 _(2,4_di- oxy odor. Sodium pyridine) methyl _2_A Oxybenzamide methyl]phenoxy]benzamide [108]

Add the triethylamine (〇22 mL' 1.58 mmol) to the solution of the compound of Example 29 (351 mg of 〇72 mm〇i) in dimethyl decylamine solution (2 mL) with ice-cooling and stirring. , diethyl cyanophosphonate (〇13 rainbow, 〇79 mm〇1) and stirred under the same conditions for 1 minute, and then added 〇5]^ ammonia/1,4-dioxane solution to the reaction mixture ( 2.88 11^, 1.44111111〇1) and stir for 3 hours at room temperature. After adding 1 N hydrochloric acid to the reaction mixture to make pH=3, extraction was carried out with chloroform/methanol = 10/1 (30 mL×3^, the combined base layer was washed with saturated brine (30 mL), and then anhydrous sulfuric acid was used. The sodium was dried to concentrate the reaction mixture. The residue was purified by silica gel column chromatography ( </ br> </ br> </ br> </ br> </ br> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI>

The title compound (88 j mg, 25%) was obtained as a powdery crystal. melting point: 208-210 ° C 2739.7, 1763.4, 1709.0, ^14.8, 1345.6, 1246.9, IR (ATR): 3379.2, 3247.7, 2985.8, 1638.5, 1609.9, 1503.9, 1460.5, 1231.0, 1171.7, 1103.7, 1014.4, 940.9, 850.4, 764.5, 686.9, 597.9, 530.4, 416.2 cm·1 ° 'H-NMR (DMSO-d6, 400 MHz) δ 3.79 (2Η, s) , 3.87 (3Η, s), 4.39 (2H, s), 4.49 (2H, d, J=6.1 Hz), 6.97 (2H d J=8 5

Hz), 7.05 (2H, d, J = 8.5 Hz), 7.12 (1H, d, J = 8.5 Hz), 7.27 (1H, brs), 7.34-7.40 (3H, m), 7.64 (1H, d, J =2.4 Hz), 7.84- 7.93 (3H, m), 8.73 (1H, t, J = 6.1 Hz), 10.9 (ih, s). EIMS (+): 489.2 [M]+. HREIMS (+): 489.17765 (calculated as C26H25N4〇6 is 489.17741). [Example 31] 5-(2,4-di- oxoxym0-yl-1-yl)methyl-2-decyloxy_n-[4-(4-pyroxy)phenyl曱基]benzamide hydrochloride [化109]

In Example 16 (1.40 g, 2.53 mmol) in methanol solution (12 6 mL) 158356.doc -114- 201212913 Add 4 N chlorinated ethyl acetate solution (丨2.6 mL) and at room temperature Search for 7 hours. 5 N aqueous sodium hydroxide solution was added to the reaction liquid under ice cooling to make the liquidity into PH 6-7, and then ethyl acetate and methanol were distilled off under reduced pressure, and then extracted with a chloroform-methanol mixed solvent (5:1). Times. The base layers were combined and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The title compound (1.186 g, 2.43 mmol, &lt;RTI ID=0.0&gt;&gt; White solid IR (ATR): 3409.2, 3157.6, 2939.9, 2720.9, 2480.2, 1757.8, 1713.4, 1643.4, 1608.3 cm·1. !H-NMR (DMSO-d6, 400 MHz) δ 1.70-1.79 (2Η, m), 2.00-2.07 (2Η, m), 2.96-3.02 (2H, m), 3.16-3.21 (2H, m), 3.78 (2H, s), 3.86 (3H, s), 4.38-4.41 (4H, m), 4.54-4.59 (1H, m), 6.94 (2H, d, J=8.9 Hz), 7.12 (1H, d, J =8.6 Hz), 7.24 (2H, d, J=8.9 Hz), 7.36 (1H, dd, J=2.4, 8.6 Hz), 7.61 (1H, d, J=2.4 Hz), 8.64 (1H,t, J =6.1 Hz). ESIMS (+): 453.2 [M+H]+. HRESIMS (+): 453.21432 (calculated as C24h29N405 453.21379) 〇 [Example 32] 5-(2,4-di- oxy imidazolidin-1-yl)methyl-2-methoxy-; -[4-(1^-Ethyl-4-ylpiperidinyloxy)phenylmethyl]benzamide [110] . 5 158356.doc -115- 201212913 Λ ο

Add acetic anhydride (0.150 mL) and triethylamine (0.092 mL, 0.663 mmol) to a solution of the compound of Example 31 (3 mg, 0.613 mmol) in THF (6.64 mL) Stir for 24 hours. The solvent was evaporated under reduced pressure, and water was added to the residue.

The ethyl acetate layer was combined and dried over anhydrous sodium sulfate. The title compound (265 mg, 0-536 mmol, 87%) was obtained. Colorless amorphous IR (ATR): 3389.5, 293 1.9, 1765.6, 1718.6, 1635.3, 1507.9 cm'1 ° H-NMR (CDC13, 400 ΜΗζ) δ 1.75-1.96 (4H, m), 2.12 (3H, s) , 3.37-3.43 (1H, m), 3.62-3.76 (3H, m), 3.78 (2H, s), 3.94 (3H, s), 4.53 (3H, s), 4.61 (2H, d, J=5, 5 Hz), 6.89 (2H, d, J-8.6 Hz), 6.99 (1H, d, J=8.6 Hz), 7.29 (2H, d, J=8.6 Hz), 7.40 (1H, dd, J=2.4, 7.9 Hz), 7.60 (1H, s), 8·14-8·17 (2H, m). ESIMS (+): 495.2 [M+H]+. HRESIMS (+): 495.22485 (calculated as C26H3iN4〇6 is 495.22436) *&gt; Elemental analysis·actual measured value C 61.51 %, H 6丨7%, N i Q , 158356.doc -116- 201212913 as C26H3 ( ) N4〇6.0·7Η2Ο Calculated value C 61.58%, Η 6.24%, Ν 11.05%. [Example 33] 5-(2,4-di-side oxyimidazolidin-1-yl)indenyl-2-methoxy-indole-[4-(indolyl-4-piperidinyloxy) Phenyl indenyl]benzamide [111] α /

Add a 37% aqueous solution of citric acid (〇.〇59 mL, 0.729 mmol) to a solution of the compound of Example 3 1 (300 mg, 0·613 mmol) in dioxane and tetrahydrofuran (6.64 mL). Triethylamine (0.092 mL, 0.663 mmol) was stirred at room temperature for 1 hour. Additional sodium triethoxysulfonate (1 83 mg, 0.862 mmol) was added and stirred at room temperature for 7 h. A 37% aqueous solution of citric acid (0.059 mL, 0.729 mmol) and sodium triethyloxyborohydride (183 mg, 0.862 mmol) were added and stirred at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the organic solvent was taken away under reduced pressure, and then the insoluble material was filtered. The filtrate was extracted twice with ethyl acetate. The ethyl acetate layer was combined and dried over anhydrous sodium sulfate, and then the solvent was evaporated. The obtained residue was combined with the filtered solid, using an automated column chromatography system (Biotage, KP-sil 25 g, gas: methanol; Biotage, KP-158356.doc • 117- · «&lt;» 201212913 NH The title compound (92 mg, 0.197 mmol, 32%). Colorless amorphous IR (ATR): 3388.2, 2939.8, 2799.5, 1765.1, 1715.8, 1643.3, 1530.3, 1507.9 cm-1 ° ^-NMR (CDC13, 400 MHz) δ 1.80-1.88 (2Η, m), 1.98-2.03 (2H,m), 2.30 (5H,m), 2.69 (2H, s), 3.78 (2H, s), 3.93 (3H, s), 4.30 (1H, s), 4.53 (2H, s), 4.61 ( 2H, d, J=5.5 Hz), 6.89 (2H, d, J=5.5 Hz), 6.98 (1H, d, J=8.6 Hz), 7.27 (2H, d, J=8.6 Hz), 7.40 (1H, Dd, J=2.4, 8.6 Hz), 8.11-8.14 (2H, m) 0 ESIMS (+): 467.2 [M+H]+. HRESIMS (+): 467.22893 (calculated as C25H31N405 calculated as 467.22944) ° Elemental analysis: Actual measured value C 62.55%, H 6.55%, N 11.62%, as C25H30N4O5 . 0·7Η2Ο Calculated value C 62.67%, Η 6·61 %, N 11.69%. [Example 34] 3-(2,4-Di-Ethyl imidazolidin-1-yl)methyl-4-methoxy-N-[4-(4-fluorophenoxy)phenylmethyl] Benzoylamine first step 3-mercapto-4-indolyl-N-[4-(4-fluorophenoxy)phenylmethyl]benzoinamine [111] 158356.doc -118 - 201212913 ο

CHO OMe added 3-B in 3-Butyl·4·methoxybenzoic acid (784, 匪 之 N, N 曱 曱 曱 曱 amine solution (12 mL) in ice bath cooling Amine (0.61 mL ' 4.35 mmol), chloroacetic acid ethyl acetate (〇 44 mL, 4 57 mmol) and stirred for 1 〇 min under the same conditions. Then, [4_(4-fluorophenoxy) was added to the reaction mixture. Phenylhydrazinyl]amine hydrochloride (1.21 g, 4.79 mmol) and stirred under the same conditions for 2 hrs. The reaction mixture was poured into ice water and 丨N hydrochloric acid was added to make 4, after which it was carried out with acetic acid Extraction (40 mL×3) The combined base layer was washed with saturated brine (4 mL), and the reaction mixture was concentrated with anhydrous sodium sulfate. The residue was purified by a gel column chromatography (Biotarge; The title compound (1.29 g, 78%) was obtained from EtOAc (EtOAc: EtOAc: EtOAc) 1635.3, 1604.0, 1542.9, 1491.1, 1415.7, 1315.9, 1246.0, 1208.8, 1188.7, 1105.4, 1015.3, 920.3, 827.2, 762.7, 691.4, 648.3, 564.2, 523.8, 502.1 cnT1. !H-NMR (CDCI3, 400 MHz) δ 4.00 (3Η, s), 4.59 (2H, d, J=5.4 Hz), 6.67 (1H, t, J =5.4 Hz), 6.92-7.05 (6H, m), 7.08 (1H, d, J=8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 8.14 (1H, d, J=2.4 Hz), 8.23 (1H, dd, J=8.5, 2.4 Hz), 10.4 (1H, s).

We &lt;〇er 158356.doc -119- 201212913 EIMS (+): 379 [M]+. HREIMS (+): 379.1205 (calculated as C22H18FN04 379.1220) ° Second step 2-[5-[[4-(4-Fluorophenoxy)phenylmethyl]amine fluorenyl]-2-A Methyl oxyphenylmethyl]aminoacetate [Chem. 113]

Add the triethylamine (0.69 mL, 4.94 mmol), the compound of the first step, in a solution of the ruthenium glycinate (620 mg, 4.94 mmol) in dichloromethane (9.4 mL) with ice-cooling and stirring. (1.25 g, 3.29 mmol), sodium triacetoxyborohydride (1.05 g, 4.94 mmol), acetic acid (0_28 mL, 4.94 mmol). A saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with ethyl acetate (30 mL×3). The base layer was combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) IR (ATR): 33 15.2, 2950.4, 2840.2, 1738.1, 1634.2, 1607.9, 1494.6, 1436.9, 1316.4, 1249.9, 1209.6, 1145.8, 1025.6, 909.0, 876.6, 827.6, 729.4, 627.5, 502. cm·1. 158356.doc -120- 201212913 'H-NMR (CDC13, 400 MHz) δ 3.42 (2H, s), 3.70 (3H, s), 3.82 (2H, s), 3.88 (2H, s), 4.60 (2H, d, J=5.4 Hz), 6.38 (1H, t, J=5.4 Hz), 6.90 (1H, d, J=8.5 Hz), 6.92-7.06 (6H, m), 7.32 (2H, d, J=8.5 Hz), 7.68 (1H, d, J=2.4 Hz), 7.78 (1H, dd, J=8.5, 2.4 Hz. ESIMS (+): 453.2 [M+H]+. HRESIMS (+): 453.18298 (as c25h26FN205 The calculated value is 453.18257). The third step is 3-(2,4-di-side oxyimidazolidine-1-yl)methyl-4-indolyloxy-1^-[4-(4-fluorophenoxy) Phenylmethyl]benzamide [化114]

Add potassium cyanate (260 mg, 3.21 mmol) to a solution of the second step (1.21 g, 2.67 mmol) in acetic acid (7.6 mL) and stir at room temperature for 30 min. 5 hours. Water was added to the reaction mixture and extracted with ethyl acetate (3 mL) &lt;3&gt;. The combined base layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (Biotarge; SNAP Cartridge KP-Sil; hexane: ethyl acetate), followed by wet milling (hexane/ethyl acetate = 1/1). The crystallization method obtained the title compound 158356.doc •121- 201212913

(1.08 g, 87%). Melting point: 115-118 ° C 1764.5, 1717.4, 1323.8, 1251.9, .4, 830.4, 762.5, IR (ATR): 3374.7, 3129.2, 3032.7, 2756.4, 1630.7, 1555.7, 1496.9, 1460.9, 1353.6 1210.3, 1187.0, 1123.9 , 1026.6, 995.5, 851 693.7, 624.9, 551.7, 506.8, 419.1 cm·1. ^-NMR (DMSO-d6, 400 MHz) δ 3 86 , •, Sichuan, s), 3.88 (2H, s) 4·41 (2H, s), 4.44 (2H, d, J = 5.5 HZ), 6.94 (2H d Bu

Hz), 6.98-7.06 (2H, m), 7.09 (2H, d 6 u, 8 6 5 «·6 Hz), 7.15-7.24 (2H, m), 7.31 (2H, d, J=8.6 Hz), 7 69 π tr UH, d, j=2.4 Hz)

7.88 (1H, dd, J=8.6, 2.4 Hz), 8.94 ΠΗ t T V t, J=5.5 Hz), 10 9 (1H, s). h ESIMS (+): 464.2 [M+H]+. The calculated value of 5 is HRESIMS (+): 464.16166 (as C25H23FN3〇 464.16217). [Example 35] 5-(2,4-di-oxy-8m,3.diazaspiro[45]pyrrolidyl)-methyl-2-oxime-Ν-[4-(4·说Phenoxy) phenylmethyl]benzamide&lt;First Step 4-[3-[[4-(4-Fluorophenoxy)phenylmethyl]aminoindolyl]_4_methoxy Phenylmethyl]amino-tetrahydro-2Η-indol-4-carboxylic acid methyl ketone [Chemical 115] 158356.doc -122- 201212913

Add 3-ethylamine to a solution of 4-aminotetrahydro-2H-pyran-4-carboxylic acid oxime ester hydrochloride (464 mg, 2 37 mmol) in dichloromethane (5 mL) (0.33 mL ' 2.37 mmol), the compound of Reference Example 1 (6 〇〇 mg, 1 · 5 8 ππποί), diethylene ethoxylated sodium nitride (5 〇 2 mg, 2.37 mmol), acetic acid (0.14 mL, 2.37 mmol) 'and stir at room temperature for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the mixture and the mixture was extracted with ethyl acetate (30 mL &lt;&lt;&gt;&gt;&lt;3&gt;&gt;&lt;3&gt;, and the base layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. . The residue was purified by silica gel column chromatography ( EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc . IR (ATR): 3401.5, 3325.7, 2959.1, 2853.6, 1727.2, 1644.4 Γ &gt; 1535.8, 1498.6, 1420.8, 1362.1, 1279.1, 1246.9, 1210.0, 1091.5, 1025.8, 980.3, 928.9, 879.7, 825.4, 781.0, 758.3, 688.0 , 614.9, 567.5, 504.5, 466.2 cm·1 〇^-NMR (CDC13, 400 MHz) δ 1.66-1.74 (2H, m), 2.03-2.14 (2H, m), 3.56-3.65 (4H, m), 3.77 (3H, s), 3.88-3.97 (5H, m), 4.65 (2H, d, J=6.1 Hz), 6.92-7.06 (7H, m), 7.32 (2H, d, J=8.6 Hz), 7.45 ( 1H, dd, J=8.3, 2.1 Hz), 8.16-8.24 (2H, m) 〇ESIMS (+): 523.2 [M+H]+. 158356.doc -123- 201212913 HRESIMS (+): 523.22516 (calculated as 523.22444) 〇Second step 5-(2,4-di-oxy _8_oxa", diaza snail [4 ^decane d-yl) fluorenyl-2-methoxy-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide [Chemical 116]

Add potassium cyanate (150 mg, 1.85 mmol) to the first step of the compound (806 mg, 1.54 mmol) in acetic acid (5 mL) and stir at room temperature for 30 min. Stir under 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate (3 mL) &lt;3&gt;. The combined base layer was washed with saturated brine (3 mL), and dried over anhydrous sodium sulfate to concentrate the reaction mixture. The residue was subjected to columnar column chromatography (Biotarge; SNAP Cartridge KP-Sil; The title compound (686 mg, 83%) was obtained from m.

Melting point: 90-93 ° C IR (ATR): 2948.0, 1763.5, 1715.5, 1646.0, 1530.7, 1494.9, 1414.4, 1349.0, 1246.6, 1209.9, 1099.6, 1013.6, 933.4, 818.3, 771.0, 714.4, 633.0, 564.5, 504.5 , 431.3 cm·1. ^-NMR (DMSO-d6j 400 MHz) δ 1.52 (2H, d, J = 12.8 Hz), 158356.doc -124- 201212913 1.86 (2H, td, J=13.0, 5.1 Hz), 3.70 (2H, dd, J=ll 〇49 Hz), 3.83-3.93 (5H, m), 4.43-4.49 (4H, m), 6.95 (2H d J=9.2 Hz), 7.00-7.05 (2H, m), 7.09 (1H} d , J=8.6 Hz), 7 i6-7.24 (2H, m), 7.33 (2H, d, J=8.6 Hz), 7.42 (1H, dd, J=8 6 2.4 Hz), 7.73 (1H, d, J =2.4 Hz), 8.69 (1H, t, J=6.l Hz) 11_0 (1H, s). ESIMS (+): 534.2 [M+H]+. HRESIMS (+): 534.20472 (calculated as C29H29FN3〇6 534.20404) ° The usefulness of the compound of the present invention is shown in Test Examples 1 to 3. <Test Example 1: Denovo (regeneration) lipid synthesis energy inhibition> HepG2 cells were cultured for 48 hours in a 12-well plate, and then replaced with blood-free, raw medium (FCS free/DMEM) and cultured for 16 hours. Then, HepG2 cells were substituted into a serum-free medium containing the test compound, [i-MC]-labeled acetic acid, and unlabeled acetic acid, followed by incubation for 3 hours. After the cultivation, the reaction was stopped by adding methanol, and thereafter, the reaction liquid was recovered. After adding chloroform to the reaction mixture and performing shaking extraction, the lower layer (chloroform) was collected and dried. After repeating a series of extraction operations, the dried product was dissolved in f alcohol and the radioactivity was measured using a scintillation counter. The test results are shown in Table 4. In addition, the "inhibitory activity" in the table does not use the de n〇v〇 lipid synthesis inhibitory activity when the test compound is 30 μΜ, and the inhibition ratio is 81% to 1%, and the inhibition ratio is 51% to 8%. 〇% is recorded as B, the inhibition ratio is 21%~50%, and the inhibition ratio is 1〇%~2〇% is recorded as D 〇158356.doc •125· 201212913 [Table 4]

EXAMPLES Inhibitory Activity Examples Inhibitory Activity 1 A 13 A 3 A 16 C 7 B 17 C 9 C 22 A 11 C 27 A As shown in Table 4, the compounds of the present invention were confirmed to have potent inhibition of de novo lipid synthesis. active. &lt;Test Example 2: ΑΜΡΚα and ACC1 phosphorylation promoting action&gt; HepG2 cells cultured in Dube-modified Eagle's medium (FCS/DMEM) containing 10% bovine serum and 1% penicillin-streptomycin (6) The cm2 culture dish was cultured in serum-free medium (FCS free/DMEM) for 16 hours, and then cultured in a medium containing the test compound for 3 hours (37 ° C, 5% carbon dioxide). After 3 hours, the cell lysate was recovered, and the amount of protein was quantified by the Bradford method (Coomass Brilliant Blue method), after which phosphorylated AMPKa (pThrl72) and phosphorylated ACC1 (pSer79) were detected by SDS-PAGE and Western blotting. The test results of phosphorylation of AMPKa (Thrl 72) are shown in Table 5. In addition, "EC50" in the table indicates the concentration of the test compound when the test compound shows 50% of the maximum effect of the phosphorylation energy of AMPKa (Thrl72), and EC5〇&lt;l is denoted as A, 1 jxN1 <EC5〇&lt;5 Μ Μ is B ' 5 jxM! &lt; EC5 〇 is C. 158356.doc -126- 201212913 [Table 5] (AMPKa (Thrl72) phosphorylation)

EXAMPLES EQ〇 3 A 7 C 22 C The test results of phosphorylation of ACCl (Ser79) are shown in Table 6. In addition, "EC5G" in the table indicates the concentration of the test compound when the test compound shows 50% of the maximum effect of the phosphorylation energy of ACCl (Ser79), and EC5Q &lt;1 μΜ is recorded as A '1 (·ΐΜ!&lt;ΕC5〇 &lt;5 § is B, 5 C5. Recorded as C. [Table 6] (ACCl (Ser79) phosphorylation)

EXAMPLES ECs〇 3 B 7 B 22 A As shown in Tables 5 and 6, the compound of the present invention was confirmed to have a good AMPKa phosphorylation promoting action and an ACC phosphorylation promoting action. &lt;Test Example. 3: Reduction of glucose and triglyceride in blood of mice&gt; Β6. V-Lep&lt;ob&gt;/J(ob/ob) male mouse (Sakamoto Charles River) as OA-2 The feed (Cochlear, Japan) was tested from 7 weeks of age after feeding from 6 weeks of age. The test compound (30 mg/kg) was suspended in a 0.1% Tween 80 (Tween 80) solution under satiety condition and continuously orally administered for 7 days once a day. After 7 days, blood was collected from the tail vein and the blood glucose and triglyceride were measured by the enzyme method. The test results are shown in Table 7. Furthermore, the "reduction rate" in the table indicates the average blood glucose amount (or the average amount of triglyceride) from the vehicle control group. 158356.doc - 127- 201212913 minus the average blood glucose of the test compound administration group The ratio of the amount of the amount (or the amount of the average triglyceride) to the amount of the average blood glucose (or the amount of the average triglyceride) of the vehicle control group, 20% < reduction rate &lt; 30% is recorded as A, 10 % &lt; reduction rate &lt; 20% is denoted as B, 1% &lt; reduction rate &lt; 10% is denoted as c. [Table 7]

EXAMPLES Reduction rate Triglyceride in blood glucose 3 B ~A ~ 7 B 22 BA As shown in Table 7, the compound of the present invention was confirmed to have a good glucose lowering effect in mice and a decrease in triglyceride effect. The present invention has been described in detail with reference to the specific embodiments of the invention, and it is obvious to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention. The present patent application (Japanese Patent Application No. 2010_187713), the entire disclosure of which is incorporated herein by reference. INDUSTRIAL APPLICABILITY The novel benzylhydantoin derivative of the present invention and its addition salt can have an advantageous effect derived from the activation of ΑΜρκ, for example, for lowering blood sugar, since it has excellent human AMPK activation. Agent or hypolipidemic drug. 158356.doc -128-

Claims (1)

201212913 VII. Patent application scope: 1. A uremone derivative or a pharmacologically acceptable salt thereof or a hydrate thereof, which is represented by the formula (1), [Chemical Formula 1] [In the formula (1), R1 represents a hydrogen atom, a Ci~C6 alkyl group which may have a substituent, a C3 to C6 cycloalkyl group which may have a substituent, a C6~Ci〇 aryl group which may have a substituent, may have a substitution a 5- or 6-membered aromatic heterocyclic group or a condensed heterocyclic group which may have a substituent, and X represents a C丨~C4 alkyl group, and a C2~C4 extension. Alkenyl group, C2~C4 stretching alkynyl group or formula (2), Y represents a single bond, C^CU alkyl group or formula (5), z represents a hydrogen atom, a halogen atom, and a Ci~C6 which may have a substituent An alkyl group, a C3 to C6 cycloalkyl group which may have a substituent, an oxy group which may have a substituent, a C3 to C6 cycloalkoxy group which may have a substituent, a hydroxyl group, a nitro group, a cyano group, an amine which may have a substituent a C6-c10 aryl group which may have a substituent, an aromatic heterocyclic group which may have a substituent of 5 or 6 members, a condensed heterocyclic group which may have a substituent, and a C7-Cu aralkyl which may have a substituent a C6~Ci aryloxy group which may have a substituent, a c7~Ci2 aryl oxyoxy group which may have a substituent, a C 1-6 C6 alkylthio group which may have a substituent, and a C6 to C1G aryl group which may have a substituent Or a C7~ci2 arylalkylthio group which may have a substituent, and the ring A and the ring B are the same or different, and represent a C3~C6 cycloalkane which may have a substituent 158356.doc 201212913, a 5 member or 6 which may have a substituent a saturated heterocyclic group, a C6~C1()aryl group which may have a substituent, a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent or a condensed heterocyclic group which may have a substituent, R2 and R3 The same or different, representing a hydrogen atom, a Ci~C6 alkyl group which may have a substituent, a C3~C6 cycloalkyl group which may have a substituent, a C6~C1() aryl group which may have a substituent or a substituted aralkyl group a group, or R2 is bonded to R3 and together with a carbon atom bonded to R2 and R3, represents a general formula (6)], (2), Ding, (2) [In the formula (2), T represents a single bond, Stretching base, c2~C4 extended alkenyl group or C2~C4 stretching alkynyl group; U represents a single bond, (^~C4 alkylene group or C2~C4 extended alkenyl group; A represents a carbonyl group, an oxygen atom, _S(0)p_ (p represents an integer selected from 〇~2), -nr4-(r4 represents a hydrogen atom, a Ci~C6 alkyl group which may have a substituent, a C7-Ck aralkyl group which may have a substituent, and a c6 which may have a substituent ~Ci〇 aryl, can Substituted Ci-C: 6 aliphatic fluorenyl group, C^-C:6-alkylsulfonyl group which may have a substituent, 5 or 6 membered aromatic heterocyclic group which may have a substituent or may have a condensed heterocyclic group of a substituent), -N(r5)s〇2_, -S〇2N(R5)- (R5 represents a hydrogen atom, may have a substituent, or may have a substituent Alkyl group, formula or formula (4)] [Chemical 3] lS8356.doc (3) 201212913 [In the formula (3), L1 represents a single bond, an oxygen atom or _Nr\, and R5 represents the same as the above. Meaning] [Chemical 4] 〇&gt;People|_, (4) R5 [In the formula (4), 'L2 represents a single bond or an oxygen atom, and R5 represents the same meaning as the above] [Chemical 5] -(CH2)h -Qi-(CH2)r (5) [In the formula (5), 'Q1 represents an oxygen atom' _S(〇)q_ (q represents an integer selected from 〇~2), -NR6- (R6 represents a hydrogen atom, may have a substituent of a CfC!2 aralkyl group which may have a substituent, a C6~C1q aryl group which may have a substituent, a CrC6 aliphatic fluorenyl group which may have a substituent, may have a substituent iCi -q alkylsulfonyl, 5 or 6 membered aromatic heterocyclic groups which may have a substituent or may have a substituent Condensed heterocyclic group) or carbonyl group, h and j are the same or different and represent an integer of 〇~2] [6] [In the formula (6), Q2 represents a single bond, a methylene group, an oxygen atom, - S(0)r-(r represents an integer selected from 0 to 2) or -NR7- (R7 represents a hydrogen atom, a C"C6 alkyl group which may have a substituent, a C7 to C12 aralkyl group which may have a substituent, A C6-C1() aryl group which may have a substituent, an aliphatic fluorenyl group which may have a substituent, 158356.doc 201212913 an alkylsulfonyl group which may have a substituent, a 5 member or a 6-shell fragrance which may have a substituent a heterocyclic group or a condensed heterocyclic group which may have a substituent), m and η being the same or different or 2]. 2. The uret urea derivative of claim 1 or a pharmacologically acceptable salt thereof or a hydrate thereof, wherein in the above formula (1), X represents a Cl~C4 alkyl group or a formula ( 2a), [Chem. 7], D1 A1, U1〆(2a) [In the formula (2a), T1 represents a single bond or c!~C4 extended alkyl group, U1 represents a single bond or an alkyl group, and A1 represents an oxygen atom. , sulfur atom, _NR4a- (R4a represents a hydrogen atom, a Ci-C6 alkyl group which may have a substituent or a C7~C 2 aralkyl group which may have a substituent), -N(R5a)S〇2_, -S〇 2N(R5a)-(R5a represents a ruthenium atom or a Ci~C6 alkyl group which may have a substituent or a c7~c12 aromatic group which may have a substituent), a formula (3a) or a formula (4a)] ] (3a) [In the formula (3 a), Lla represents a single bond or _NR5a-, and R5a represents the same meaning as the above] [Chemical 9] 158356.doc 201212913 ο, person (4a) R5a [in the formula (4a) 'R5a means the same meaning as the above.'. 3. The uret urea derivative of claim 1 or 2, or a pharmacologically acceptable salt thereof, or a hydrate thereof, wherein in the above formula (1), χ represents a formula (2b), 10] butyl 1 - A2_ (2b) [In the formula (2b), Τι denotes a single bond or a Ci~C4 alkyl group, and a2 represents a formula (儿) or a formula (4a)] [11] Ο 'N ^^N〆(北) II R5a' R5a [R in the 弋() represents a hydrogen atom or a Ci~C6 alkyl group which may have a substituent or a pharmaceutically-substituted substituent The same meaning] [Chemical 12] 〇 (4a) R5a [In the formula (4), '^ indicates the same meaning as the above). 4. The urelic urea derivative or the pharmacologically acceptable salt of 158356.doc 201212913 or the hydrate thereof as claimed in any one of claims 1 to e, wherein in the above formula (丨), 2 represents a hydrogen atom, a halogen atom, an amine group which may have a substituent, such as a 6-alkoxy group, a C3 to C6 cycloalkoxy group which may have a substituent, a nitro group, a cyano group, and a substituent group, may have Substituent C; 6~C 1Q aryloxy, C7~C]2 aralkyloxy group which may have a substituent, Cl~c6 thiol group which may have a substituent, Cg-C 1 which may have a substituent () an arylthio group or a c7~c12 aryl thio group which may have a substituent. 5. The carbendazole derivative of any one of claims 1 to 4 or a pharmacologically acceptable salt thereof or the like a hydrate in which the ring A and the ring B are the same or different in the above formula (i), and represent a C3 to C6 cycloalkyl group which may have a substituent, a C6 to C1G aryl group which may have a substituent, and may have a substituent. a saturated heterocyclic group of 5 or 6 members, an aromatic heterocyclic group which may have a substituent of 5 or 6 members, or a condensed heterocyclic group which may have a substituent. The term acyl urea, hydantoin derivative or a pharmaceutically do the valleys of such salts or hydrates, wherein in the general formula (Shu) ring A table nowhere formula (7) [of 13] V&gt; (7) [In the formula (7), V1, V2, V C-R8 (R8 represents a hydrogen atom, V and V4 are the same or different, and represent a nitrogen atom or a halogen atom, an alkyl group which may have a substituent, and may be a c3~c6 cycloalkyl group having a substituent, a Cl~alkoxy group which may have a substituent, a c3~c6 cycloalkoxy group which may have a substituent, a hydroxyl group, 158356.doc 201212913 nitro group, cyano group, hydroxycarbonyl group, Alkoxycarbonyl group, amine group which may have a substituent, c6~c1Q aryloxy group which may have a substituent, c7~c12 aralkyloxy group which may have a substituent, Ci~(:6 alkyl sulfide which may have a substituent a C6~C1Q arylthio group which may have a substituent or a c7~c12 arylthio group which may have a substituent.] 7. A carbendazim derivative or a pharmacologically acceptable salt thereof or the like a hydrate represented by the formula (1 a), [Chem. 14] a C3~C6 cycloalkyl group which may have a substituent, a C6~c丨❹ aryl group which may have a substituent or a C7~c丨2 aralkyl group which may have a substituent, and ^ represents a formula (2c), Y The formula is not a single bond, a methylene group, an oxygen atom, a sulfur atom or -NR6a- (R6a represents a hydrogen atom or a C1-C6 alkyl group which may have a substituent), and z represents a hydrogen atom, and a Ci~C6 alkane which may have a substituent The oxy group may have a c3 to c6 cycloalkoxy group or a substituent which may have a substituent. Aryloxy, :A represents a C6~Ci which may not have a substituent. An aryl group or an aromatic heterocyclic group which may have a substituent or a member of 6 members, a C3 to C6 ring-burning &amp; which may have a substituent, and a 5-membered or 6-membered saturated heterocyclic group which may have a substituent C6~ci which may have a substituent. An aryl group or a 5-membered or 6-membered aromatic heterocyclic group which may have a substituent, 158356.doc 201212913 R 3 and R 3a are the same or different and each represents a hydrogen atom, a c-C0 alkyl group which may have a substituent, and may have a c3~c6 cycloalkyl group of a substituent or a C6~C1() aryl group which may have a substituent, or a "same" which is bonded to a ring and which is bonded to a carbon atom bonded to R2a&amp; R3a, represents a general formula (6a)] [Chem. 15] —T2—A3 - (2C) [In the formula (2c)? T2 represents a single bond or a methylene group, and A3 represents a formula (3c) or a formula (4b)] [Chemical Formula 16] OAW NIR 3C [In the formula (3c), the same or different, represents a hydrogen atom or may have a substituent C 1~C 6 炫 base] [Chemical 17] (4b) Λ R5b [In the formula (4b), R5b represents the same meaning as the above] [Chem. 18] (6a) [Formula (4)] Q, list Bond, methylene group, oxygen atom 158356.doc 201212913 -NR7a- (R7a represents a hydrogen atom or a Cl~c6 alkyl group which may have a substituent), and m and η are the same or different and represent 1 or 2]. 8_ wherein the uret urea derivative of claim 7 or a pharmacologically acceptable salt thereof or the hydrate of the above is represented by the formula (lb), [Chem. 19] [In the formula (lb), 'Rlb represents a hydrogen atom, a Cl~C6 alkyl group, a C3~C6 cycloalkyl group or a formula (8), and Xb represents a formula (9), a formula (1〇) or a formula (11). Wherein 0 represents an oxygen atom or a sulfur atom, Zb represents a hydrogen atom or (^~(^ alkoxy, ring VIII15 represents C6~C1() aryl or pyridyl, and ring Bb represents (1) C3~〇6 ring a base group, (2) a dentate group which may be substituted with an alkyl group, a Cl~C6 aliphatic fluorenyl group or an oxycarbonyl group, or (3) may pass through a halogen atom, a Cl~c6 alkyl group, a Cl~C&amp;oxy group, (: 2~(:7 alkoxy group, cyano group, c6~ClQ which can be substituted by one or two (:1~(:6 alkyl substituted amine group, substituted by benzyl or aminocarbonyl group) The aryl group, R2b and R3b are the same or different and represent a hydrogen atom, a Ci~C6 alkyl group, a C6~Ci〇 aryl group or a formula (12)' or a carbon atom bonded to R3b and bonded to R2b and a ruler. And represents the general formula (6b)] 158356.doc 201212913 [Chemical 20] (ch2) v-r9 (6) [In the formula (8), R9 represents a hydroxyl group, a C7-C12 aralkyloxy group or a cyclic amine of 3 to 6 members. Base, v means an integer from 1 to 6] [Chem. 21] 〇UN N Η Η (9) [Chem. 22] (10) [Chem. 23] 0 (11) [Chem. 24] (CH2) W-R10 (12) [In the formula (12), R1Q represents a hydroxycarbonyl group or a C8-C13 aralkyloxycarbonyl group, and w represents 1 to 6 Integer] [Chem. 25] 158356.doc -10- 201212913 (6b) [In the formula (6b), 'm and n mean the same meaning as the above. 9. The uret urea derivative according to claim 7 or 8 or a pharmacologically acceptable salt thereof or a hydrate thereof, which is represented by the formula (lc), [Chem. 26] Ο π [In the formula (lc), R11 represents a halogen atom, C: 2 to C7 alkoxycarbonyl group, cyano group, or may be one or two (: broad (: 6 alkyl substituted amine groups, R lb, R And Z represents the same meaning as the above. 10. The uret urea derivative of claim 1 or a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the compound represented by the above formula (1) Is (R) -5-(2,4-one-oxy-5-propyl b-indole)-methyl-2-methoxy-N-[4-(4-fluorophenoxy) Phenylhydrazinyl]benzamide, (S) 5-(2,4-one-oxy-5-propyl miso-sityl)-methyl-2-methoxy-indole-[ 4·(4-Fluorophenoxy)phenylmethyl]benzoinamine 5_(2,4-one-oxy-5,5-diindenidazolidin-1-yl)methyl_2_ Methoxy-indole-[4-(4-fluorophenoxy)phenylindolyl]benzamide, 5-(2,4-di-oxyidazolidinyl)-indenyl-2-_1 Methoxy_ν_[4_(4_gasooxy)benylmethyl]benzamide, 3-(2,4-di-oxyidazoidinyl)methyl-Ν_[4_(4-_fluorobenzene Oxy)phenyl]benzamide, 158356.doc •11- 201212913 5-(2,4-di- oxyimidazol-1-yl)methyl-2-methoxy -:^-[4-(4-Tertioxycarbonylpiperidin-1-yloxy)phenylindenyl]benzamide, 5-(2,4-di-oxyidazolidin-1 -yl)methyl-2-methoxy-N-[4-(4-fluorophenylthio)phenylmethyl]benzamide, 5-(2,4-di-oxo-8-oxygen Hetero-1,3-diazaspiro[4.5]decane-1-yl)methyl-2-methoxy-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide Amine, 5-(2,4-di-oxyimidazolidine-1-yl)methyl-N-[4-(4-fluorophenoxy)phenylindolyl]benzamide, 5-(2, 4-tertiary oxy-3-butylimidazol-1-yl)methyl-2-methoxy-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide, 5-(2,4-Di-oxo-3-cyclopropylimidazolidin-1-yl)methyl-2-methoxy-N-[4-(4-fluorophenoxy)phenylmethyl Benzoamide, 5-(2,4-di-oxy-3-(2-hydroxyethyl)imidazolidinyl-p-yl)methyl-2-decyloxy-N-[4-(4- Fluorophenoxy)phenylmethyl]phenylamine, 5-(2,4-di-oxo-3-(2-indolylethyl)imidazolidin-1-yl)indenyl-2-曱-oxy-N-[4-(4-fluorophenoxy)phenylmethyl]benzamide or 5-(2,4-di-oxyimidazolidine-1-yl)indolyl-2 -methoxy-^[-[4-(4 -Cyanopyloxy)phenylmethyl]benzoin. 11. A pharmaceutical product according to any one of claims 1 to 10, or a pharmacologically acceptable One or more of a salt or such a hydrate is an active ingredient. 12. An AMPK activating agent which is an active ingredient of an endogenous uretide derivative according to any one of claims 1 to 1 or a pharmacologically acceptable salt thereof or one or more of the hydrates . 158356.doc -12· 201212913 13. 14. 15. 16. 17. A blood lipid-lowering drug, which is a scorpion gland derivative or a squirt gun of any of the following items: One or more of the salts of the γ + π + H fly /, the music of the salt, or the hydrates of the above are the active ingredients. A prophylactic or therapeutic agent for atherosclerosis, which comprises the uremium urea derivative or a pharmacologically acceptable salt thereof or any one or more of the hydrates as claimed in any one of the above items (1) to 1 . A preventive or therapeutic agent for diabetes, which comprises the B-glycan derivative according to any one of the claims i to i 0 or a pharmacologically acceptable salt thereof or one or more of the hydrates. A preventive or therapeutic agent for obesity, which comprises the intraglycolidine derivative of any one of claims 1 to 3 or a pharmacologically acceptable salt thereof or one or more of the hydrates as an active ingredient . A cancer therapeutic agent which comprises, as an active ingredient, an endogenous uret urea derivative as claimed in any one of claims 1 to 10, or a pharmacologically acceptable salt thereof or one or more of such hydrates. 158356.doc -13- 201212913 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: 158356.doc