TW201245190A - Bicyclic pyrimidine derivative - Google Patents

Abstract

The object of the present invention is to provide a compound or a physiologically acceptable salt thereof which has a MGAT inhibitory effect and is useful as a medicament, and a pharmaceutical composition comprising the same. A bicyclic pyrimidine compound of formula (I): wherein R1 is optionally substituted lower alkyl, etc., R2 is hydrogen atom, etc., R3 is hydrogen atom, etc., R4 and R5 are each independently hydrogen atom, etc., X is oxygen atom, etc., Y is -N(R9)C(=Z)- in which R9 is hydrogen atom, etc., Z is oxygen atom, etc., etc., m is 1, n is 2, or a physiologically acceptable salt thereof.

Description

201245190 VI. Description of the Invention: [Technical Field] The present invention relates to a monocyclic pyrimidine having a monomethyl glycerol thiol transferase (m〇noaCylglyCer〇iaCyltransferase) (hereinafter, also referred to as "mgaTj"). A structural compound or a physiologically acceptable salt and a pharmaceutical composition containing the same. [Prior Art] In recent years, so-called lifestyle-related diseases such as diabetes, hyperlipidemia, and hypertension have increased remarkably. In modern society, the increase in fat tissue, that is, the increase in obesity, is a major basis for these diseases. Therefore, it is important to treat obesity. Japan treats obesity as a disease called obesity and actively publishes it. The guidelines for the diagnosis and treatment of the disease. The body mass index (body mass index) is 25 or more. The symptoms of a health disorder caused by or related to obesity and requiring weight loss are regarded as obesity. Symptoms · Type 2 diabetes, glucose imbalance, abnormal lipid metabolism, high blood, high uric acid Blood wind, coronary artery disease, cerebral infarction, sleep beer: two fatty liver, plastic surgery, menstrual abnormalities, urine protein. In addition, ^ (four) health disorders, (four) fat obesity is also considered obesity. Therapy can be carried out by diet therapy and exercise therapy. When the treatment is improved by these treatments, it is also possible to implement drug therapy for obesity drugs. It is known that there are fat absorption inhibitors for the second sex food. 'But both non-pharmaceutical effects and side effects. 2. Sibüt_ine is effective in meeting the requirements of the drug. Therefore, I61077.doc 201245190 looks forward to the development of agents that are excellent in both efficacy and side effects. Ingestion of neutral fat (triglyceride (TG)) is broken down into fatty acids and monoterpene glycerol (MG) by pancreatic lipase in the digestive tract to form micelles and is absorbed by intestinal epithelial cells. The thiol-CoA (acyl-coenzyme A) synthetase is used to form the aryl-CoA. In addition, MG and thiol-CoA synthesize dimercaptos using monoterpene glycerol thiol transferase (MGAT). Glycerin (DG), and then DG TG-CoA re-synthesizes TG using dimercaptoglycerol thiol transferase (DGAT). The synthesized TG uses microsomal triglyceride transfer protein (MTP) to associate with cholesterol vinegar and apoprotein. The chylomicrons are formed and secreted into the blood via the lymphatic vessels and transported to the peripheral tissues. As described above, MGAT catalyzes the reaction of MG with thiol-CoA to synthesize DG, and plays an important role in the absorption of fat from the small intestine. However, due to the difficulty in purification of MGAT, research has not progressed, and genetic identification is also a recent matter. To date, MGAT has been selected and reported with three molecular species (MGAT1, MGAT2, MGAT3) (see Proceedings of the Narional Academy of Sciences, 99, 8512-8517, 2002; Jounal of Biological Chemistry, 278, 18532-18537, 2003; Journal of Biological Chemistry, 278, 13860-13866, 2003; American Journal of Physiology, 285, E927-E937, 2003; Journal of Biological Chemistry, 278, 1361 1-13614, 2003). MGAT1 is expressed in the stomach or kidney and is not detected in the small intestine. On the other hand, MGAT2 performs better in the small intestine. In addition, I61077.doc 201245190 MGAT3 reports its genes only in humans, which are specifically expressed in the small intestine. Therefore, it is speculated that MGAT2 and MGAT3 participate in the absorption of fat in the small intestine. OLETF (Otsuka Long-Evans Tokushima Fatty) rats exhibiting obesity or hypertriglyceridemia have been reported to have increased MGAT activity in the small intestine, suggesting that MGAT is involved in obesity or hypertriglyceridemia (see Diabetes Research and Clinical Practice, 57, 75- 82, 2002). In addition, there are reports that obese db/db mice and DIO (diet induced obesity) mice also have increased MGAT2 protein content and increased MGAT activity in the small intestine, suggesting that they are involved in obesity (see Journal of Biological Chemistry, 279, 18878-18886, 2004). In addition, it has been reported that mice lacking the MGAT2 gene show resistance to induction of obesity and insulin resistance by a high-fat diet (refer to Nature Medicine, 15, 442-446, 2009), on the other hand, as having MGAT inhibition, and The compound described in Patent Documents 1 and 2 has been reported as a compound having a bicyclic pyrimidine structure. Further, as a compound having a GPR119 agonistic action and having a bicyclic pyrimidine structure, the compounds described in Patent Documents 3 and 4 are reported. However, specific compounds having an azetidine structure which is one of the features of the present invention are not described in the patent documents. [PRIOR ART DOCUMENT] [Patent Document 1] International Publication No. 2008/038768 [Patent Document 2] International Publication No. 20 10/095767 161077.doc 201245190 [Patent Document 3] International Publication No. 2008/ [Patent Document 4] International Publication No. 2008/130584 [Summary of the Invention] [Problems to be Solved by the Invention]

An object of the present invention is to provide a MGAT-inhibiting compound or a physiologically acceptable salt thereof which can be used as a pharmaceutical, and a pharmaceutical composition containing the same. [Means for Solving the Problem] The inventors of the present invention have been able to suppress the absorption of fat from the small intestine by inhibiting the MG AT activity in the small intestine, and have been effective in obesity. The compound having a bicyclic fenidine structure represented by the formula (1) (hereinafter also referred to as "the compound of the present invention") and a physiologically acceptable salt thereof have an MGAT inhibitory action and have a fat absorption inhibiting effect' to complete the present invention. . That is, the present invention is as follows. Π ] A bicyclic pyrimidine compound represented by formula (I) or a physiologically acceptable salt thereof: [Chemical Formula 1]

R丨 represents a hydrogen atom, a lower alkyl group which may be substituted, a dilute group, a lower cyclic group which may be substituted, a lower-order cycloalkenyl group which may be substituted and substituted, I61077.doc 201245190 may be substituted by H Substituted naphthyl or substituted, saturated or unsaturated heterocyclic group, denotes a gas atom, a lower alkyl group which may be substituted, a lower cyclizable group which may be substituted, a lower alkynyl group which may be substituted, may be substituted Lower cyclohexyl, lower substituted cycloalkenyl, substituted lower alkyl fluorenyl, substituted phenyl group, substituted phenyl, substituted naphthyl or substituted a saturated or unsaturated heterocyclic group, R 3 represents a hydrogen atom, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted lower cycloalkyl group, and a lower ring which may be substituted An alkenyl group, a substituted phenyl group, a substituted naphthyl group or a substituted saturated or unsaturated heterocyclic group, wherein R3 is not a benzamidine group, and R4 and R5 each independently represent a hydrogen atom, Halogen atom, lower calcination group which can be substituted, C3 which can be substituted 6 cycloalkyl, hydrazine H or 0R4b (wherein R4b represents a C1 -6 alkyl group or a substituted c3_6 ring group which may be substituted), and X represents an oxygen atom, a sulfur atom, -N(r6)K (r7) (r8h in the formula, r6 represents a hydrogen atom, a lower alkyl group which may be substituted or a substituted phenyl group, or R2 and R6 may together form a cyclic amino group, which independently represents a hydrogen atom, a dentate atom, A lower alkyl group which may be substituted, a C3.6 ring group which may be substituted or a substituted phenyl group or R7 and R8 may together form a cycloalkyl ring), and Y represents a formula (II) , (III), (IV) or (V): [Chemical 2] 161077.doc 201245190

And father again. (4) (IV) (wherein R9 represents a hydrogen atom, a lower alkyl group which may be substituted, a lower cycloalkyl group which may be substituted, a phenyl group which may be substituted or a saturated or unsaturated group which may be substituted The heterocyclic group 'Z represents an oxygen atom or a sulfur atom), m represents 1, and η represents 2]. [2] The bicyclic pyrimidine compound of [1] or a physiologically acceptable salt thereof, wherein the bicyclic pyrimidine compound is represented by the formula (la): [Chemical 3]

[wherein, each symbol is as defined in [1]]. The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [1], wherein R1 represents the following formulas (2a'), (2b'), (2c,), The base shown by any of (2d·), (2e'), (2f·), or (2g|): [Chemical 4]

Rd2e (2e,> 161077.doc ·9· 201245190 [where,

Ra2a 'Ra2b, Ra2c, Ra2d, Rb2 'Ra2f& Ra2g independently represent a hydrogen atom, a halogen atom, a CF3, a CN, an OH, a C!-6 alkyl group, a c!.6 alkoxy group (here, the Cw alkane) The base and the C, 6 alkoxy group may be substituted by CO 2 H or CO 2 CR 1 giRi PR 1 g 3 (here, Ri gi, Ri g 2 and Ri g 3 are each independently represented by a hydrogen atom, a C!.4 alkyl group (the group may be via OH, Cw alkoxy, C3.6 cycloalkyl which may be substituted by Cw alkoxy, saturated heterocyclic group of 5 or 6 members, saturated heterocyclic oxy group of 5 or 6 members, or NR1blRlb2 substituted, Rm and Rlb2 Each independently represents a gas atom or a Ci. ig group), a C3-l〇 cycloalkyl group (the group may be substituted with 1 to 2 substituents selected from a fluorine atom and a C 4 alkoxy group), C6-1 () an aryl group (the group may be substituted by a halogen atom or a Ci 4 alkoxy group), a 5- or 6-membered saturated heterocyclic group, or a heteroaryl group of 5 to 10 members (the group may be via an alkyl group or a ci4) Alkenyl substituted), or RW and RW may form a cycloalkyl ring of a member or a 5- or 6-membered saturated heterocyclic ring together with the carbon atom to which the bond is bonded)), C,.6 alkyl Rebel, C〇2Ru, NRlbRl^c divination) NRidRie, and as long as chemistry If it is tolerable, then a2a a2b , ^ can be substituted for any number of positions.

R

R

R a2c

Ra2d, Ra2f and Ra2g, R 2n represents a hydrogen atom, cf3, cm, ek* # rn pa XTDlb , Ci.6 alkyl, Cw alkylcarbonyl C02R 'NR-R«c^C(=〇)NRldRle> 161077. Doc 201245190 R , R , Rk , Rld and Rle each independently represent a hydrogen atom or a brothel group: or R1, or Rld and RU may also form a 4 to 8 member cyclic amine group together with the respective bond 2 or Minoline,

Rd2e and Re2e independently of each other and have a plurality of groups independently represent a hydrogen atom, OH, C, .6 alkyl, C〇2H, c〇2_Ci 6 alkyl, c丨6 alkoxy or phenyl. (here, the phenyl group can pass through the dentate atom, c

J ^ 1-4 W base, COzH, COij-Ci · 6 hospital base or Cm decyloxy substitution), or Rd2e and R mountain may also form a 3-8 member with one carbon atom bonded thereto a ring-burning ring, or two bonded to a carbon atom adjacent to each other via 〇~3 carbon atoms

Rd2e may also form a 4- to 8-membered cycloalkyl ring together with the two carbon atoms bonded thereto and the carbon chain between the carbon atoms, and X2d represents an oxygen atom or -N(Re2)- (wherein R. 2 represents a hydrogen atom or a Ci i group, X2g represents an oxygen atom or a sulfur atom, I, p2c 'p2d, n2f and one represent an integer of 〇~4, n2c represents an integer of 1~6, m2d represents An integer from 1 to 3, n2d represents an integer from 0 to 3, and n2e represents an integer from 0 to 8]; R2 represents any of the following formulas (3a), (3b), (3c), (3d) or (3e) The base shown by one: [Chem. 5] 161077.doc 201245190

[In the formula, Ra3a, Ra3b, Ra3c, Ra3d, and Rb3 are each a single atom, CF3, CM' OH, CK6 alkyl, and stand for gas atom, halogen Cl-6 alkoxy (this group can be burned by C|-4) Oxygen substituted), Ci-6 hexyl group, c〇2R2a, NR2bR2c bite C(=0)NR2dR2e, and may be substituted at any position as long as it is chemically tolerable

Ra3a, Ra3b, Ra3t^Ra3d, 尺, 11, 11, 112*, and 1^ each independently represent a nitrogen atom or a ruthenium. 1 or Rle' or R2e may also be bonded to each of them. N together form a cyclic amine group of 4 to 8 members, X3d represents an oxygen atom, a sulfur atom or _N (in the Re3M formula, Re3 represents a sub or a Chq alkyl group), , η represents an integer of 0 to 6, and n3b represents 0. An integer of ～6, η represents an integer of 1 to 6, an integer of 1 to 3 is not represented by m, an integer of 0 to 3 is not represented by η, an integer of 〜8 is not represented by η]; 161077.doc •12· 201245190 6]

R3 represents a group represented by any one of the following formulas (4g), (4h) or (4i):

[in the formula,

Arm means a benzene ring or a heteroaromatic ring.

Ra4g& Ra4h independently represents a hydrogen atom, a halogen atom, a CL, a CN, an OH, a Ci-H), a C3.6 cycloalkyl group, a C6 alkoxy group, a C3 6 ring alkoxy group, and a Cw alkylcarbonyl group. , C02R3aa, NR3abR3ac, C(=C))NR3adR3ae or CH=CH-R3af (wherein R3aa, RW, R3ac, dR3ae independently represent IL atom or Cl.丨Q alkyl, or R3ab and R3ae, or ruler 3 and the ruler~ may also form a cyclic amine group of 4 to 8 members with the N bonds of the respective bonds; R3af represents CN, C02H, C02R3n or c(=〇)NR3f2R3f3, R3fi, R3f2 and respectively represent independently a hydrogen atom or a Ci0 alkyl group, and as long as it is chemically tolerable, a plurality of scales can be substituted at any position... and ...", R is called R"g, Rd4h, Re4h, Rf4h, Rg4h, Rh4h, Ri4h, Rj4h and Rk4h, and R, and "i' Rf4jRg4i are independent of each other and have a plurality of groups, respectively, independently representing a hydrogen atom, 0H, c. 6.6 alkyl, C〇2h, c〇2_Ci 6 Base, Ci 6 oxy or 161077.doc •13· 201245190 The base (here 'the phenyl can be via the atom, ci? 3, ^ C02H, C〇2-C -6 alkyl or Cw alkoxy group Or, R "g and, Rd41^R"h, Rf4iRg4h, Rh4h and R-, Rchuan and R"h, R state and Re4i, and Han (4) and Rg4i may also be associated with one of the bonds respectively The carbon atoms together form a 3 to 8 membered cycloalkyl ring or a 5 or 6 membered saturated heterocyclic ring, or 2 bonded to a carbon atom adjacent to each other via 0 to 3 carbon atoms.

Rd4g, Rd4h, Rf4h, Rh4h, Rj4h, Rd4i or Rf4i may also form a 4 to 8 membered cycloalkyl ring together with the two carbon atoms bonded thereto and the carbon chain between the carbon atoms.

Rb4h and Rb41 each independently represent a base of any of the following (i) to (xi): (i) a hydrogen atom, a (Π) halogen atom, (iii) OH, (iv) OR3bl, (v) CN, (vi) C02H, (vii) C(=0)NR3b2R3b3, (viii) S02NR3b4R3b5, (ix) NR3eC(=0)NR3b6R3b7, (here, R3b1 represents a hydrogen atom, a Cmo alkyl group or a c丨.丨) Alkane fluorenyl; R3b2, R3b3, R3b4, R3b5, R3b6, R3b7 and R3e each independently represent a hydrogen atom or a C丨-丨0 alkyl group, or R3b2 and R3b3, R3b4& R3b5, or 366 and R3b7 are also 161077. Doc •14· 201245190 can form a cyclic amine group of 4 to 8 members with N each of these bonds, and (X) any group represented by the following formula (4f): [Chem. 7]

(here, R34f represents a hydrogen atom or a Cl.1Q alkyl group), or (xi) C02CR3glR3g2R3g3 (here, R3gl' R382 and Rh3 each independently represent a hydrogen atom, C, ·4 alkyl group (this group may be subjected to 0H, c,4 alkoxy, Cw cycloalkyl which may be substituted by Ci 4 alkoxy group, saturated heterocyclic group of 5 or 6 members, saturated heterocyclic oxy group of 5 or 6 members, or NR3b8R3b9 substituted, R3bS And independently representing a hydrogen atom or a C 丨 丨〇 alkyl group, a C3-1G cycloalkyl group (the group may be 1 to 2 substituents selected from the group consisting of a fluorine atom and a Ci 4 alkoxy group) Substituted), aryl (the group may be substituted by a halogen atom *Ci4 alkoxy), a 5- or 6-membered saturated heterocyclic group, or a heteroaryl group of 5 to 10 members (the group may be via a Ci4 alkyl group or Ci.4 alkoxy substituted), or R3gl and R3g2 may form an 8-membered cycloalkyl ring or a 5- or 6-membered saturated heterocyclic ring together with the bonded carbon atom, indicating 〇~ 1〇 integer, I61077.doc •15· 201245190 m 4h fl4h ' P4h^q4h integer, and 丨 respectively represent 〇~5, r ' s and S41 respectively represent 0 or 1 (where 'in r4h is 1 Feelings When the shape 1 represents an integer of 1 to 5; in the case, m4i represents an integer 4h of ί~5 · '' 昧, Rb4h矣_ u + number 'when s is 1 and η is 0, R is not the above (1), (vii), (viii), (8), or (8), wherein Rb4i represents the above (1), (4)), (Wii), (x) or (xi) The base shown in either of them)]. [4] The bicyclic cardiac compound of any one of [1] to [3] or a physiologically acceptable salt thereof (1) represents the following formula (2a,), (10), (), (Μ), The base shown by either (2cT), (2e·) or (2g,): [Chem. 8]

[in the formula,

Ra2a, Ra2b, Ra2c, Ra2d

Rb2 and Ra2s each independently represent a hydrogen atom, a self-primary atom, cf3, C"6 炫, or a Ci6 alkoxy group (here, the 匸|-6 alkyl group and (: 1.6 methoxy group can be passed) 2^1 or (: 02 € 111811 ^ 2 183 substitutions (here, R1, Rig2 and RU3 each independently represent a hydrogen atom or a 匕-4 alkyl group (the group may be via hydrazine H, Ci 4 alkoxy, 5 or 6 members of I61077.doc -16 - 201245190 saturated heterocyclic group or NRmRlb2 substituted, and Rib2 independently represent a hydrogen atom or C, -6 alkyl))), and VIII is chemically tolerable, Substituting a plurality of Ra2a, Ra2b, Ra2c, and nRa2g at any position, and R and R independently of each other and having a plurality of groups independently represent a hydrogen atom, an alkyl group, a C!·6 alkoxy group or a phenyl group. (here, the phenyl group may be substituted by a dentate atom, Cf3, Ci-4 succinyl or C" methoxyl), or Rd2e&R&; may also form with one of the carbon atoms bonded thereto 3 a ring-shaped base ring of ~8 members, or two R gases bonded to a carbon atom adjacent to each other via 〇~3 carbon atoms may also be bonded to the two carbon atoms bonded thereto, and the carbon atom The carbon chain together form a cycloalkyl ring of 4 to 8 members, X2d represents an oxygen atom or Ν〇 (wherein 'Re2 represents a hydrogen atom or c" a base), X2g represents an oxygen atom or a sulfur atom, η, n2b, ρ, 卩2 <1 and n2g represent integers of 〇~4, n2e represents an integer of 1 to 6, m2d represents an integer of 1 to 3, n2d represents an integer of 0 to 3, and n2e represents an integer of 1 to 6]; R2 shown represents any of the following formulas (3a), (3c), and (3dut(3e). [Chemical 9] 161077.doc 17- 201245190

Wherein R, Ra3e, Ra3d & Rb3 each independently represent a hydrogen atom, a halogen atom, a CF3, a Cl.6 alkyl group, or a Cl_6 alkoxy group (the group may be substituted by a Ci·4 alkyl fluorenyl group), and Chemically, it is possible to substitute a plurality of Ra3a, Ra3c and Ra3d at any position, and x3d represents an oxygen atom, a sulfur atom or -N(Rc3)- (wherein R. 3 represents a nitrogen atom or a CN6 alkyl group) 'n3a denotes an integer of 〇~4' n3c denotes an integer of 1 to 6' m3d denotes 1 n3d denotes 〇' n3e table 〇 ' integer of R3 table system Γ, integer, integer]; the following formula (4g), The base shown in either (4h) or (4i) [10] • 18-161077.doc 201245190

[in the formula,

Arm represents a stupid or heteroaromatic ring, and R and 11 each independently represent a hydrogen atom, a halogen atom, CF3 CN, OH, C, alumina, Ci-6 alkoxy, C02R3aa, c(=〇)NR3adR_3 or CH =CH-R3af (wherein 3 3ad KR and R each independently represent a j atom or a CK6 building group, and R3af represents Co#, (3) 2R3fl or R3fl, R3f2 a D3f3, V } / Knife independently represents a hydrogen atom or a CM alkyl group ), and the eight chemistry can be changed, then the plural 4 Ra4g^Ra4h can be replaced at any position.

Rf4i and Rg4i are R and R "g, R"h, R"h, Ri4h, Rg4h, Rh4h, Ri4h, Rj~Rk4h, with >3 Rd4i, pe4i _ „f4i „ independent of each other, and plural Each base time independently represents a gas enthalpy, a Cu alkyl group, a C02H or a CCVCw alkyl group, or, RW and RW, an R state and an R "h, Rf4h, and Rg4h, Rh4h ^

Ri4h, Rj4h and Rk4h, Rd4i 4i and Rg can also form a cycloalkyl ring of 3 to 6 members, respectively, together with a carbon atom bonded to each of them, and R(4) and Rb4i independently represent the following (out) , (iv), (yi), (wi 161077.doc -19- 201245190 or (xi) as shown by: (iii) OH, (iv) OR3bl, (vi) C02H, (vii) C(=〇)NR3b2R3b3 ' (here, R3b1 represents a hydrogen atom, a Cm alkyl group or a Cl.6 alkyl alkano group; Rsb2 and R3b3 each independently represent a hydrogen atom or a Ck alkyl group, or R3b2 may also be associated with each other N-bonding forms a cyclic amine group of 5 to 7 members, and (xi) C02CR3^R3^R3®3 (here, rW, rW, and rW each independently represent a hydrogen atom or a hydrazine "alkyl group ( The group may be substituted by OH, Cm alkoxy, a 5- or 6-membered saturated heterocyclic group or NR3b8R3b9, "" and the ruler independently represent an argon atom or a C, _6 alkyl group), and m4g represents 1 to 6 The integers, m, n4h, p4h, and q4h, and n4i respectively represent integers of 〇~5, r4h, S4h, and one independently represent 〇 or 1 (where 'in the case of Hi' m4h represents 2~5 Integer; In case b, m4i represents an integer of 2 to 5; when S4h is 1 and n4h is 〇, ^_ represents the base shown in any of the above (vii) or (xi); 1 and η is the case of 〇 ' Rb4 · Table * (7) 〇 or (10) in the path shown in the road)], · R knife independently represents a hydrogen atom, a fluorine atom or can be replaced by gas Base, 16l077.doc 201245190 X represents an oxygen atom, a sulfur atom, -N(R6)- or -C(R7)(R8)- (wherein R6 represents a nitrogen atom or a Cw alkyl group which may be substituted by a fluorine atom' R7 And R8 each independently represents a nitrogen atom or a CN6 alkyl group which may be substituted with a fluorine atom. [5] The bicyclic pyrimidine compound according to any one of [1] to [4] or a physiologically acceptable salt thereof Y is a group of the formula (Π), (III) or (IV): [Chemical "] R9 (丨丨) (川) (iv) [wherein, each symbol is as defined in [丨] [6] The bicyclic (IV) compound of any one of [1] to [5] or a physiologically permissible salt thereof, wherein Y is a group represented by the formula (ΙΠ): [Chemical 12] [7] A bicyclic pyrimidine compound according to any one of [] to [6] or physiologically彳allowed salt' where R3 is a group of formula (4g): [Chem. 13]

[in the formula, 161077.doc 201245190

Arm is a benzene ring or a ° bite ring,

Ra4g represents a hydrogen atom, a halogen atom, CN, OH, CO2H, C〇2_c alkyl, or CH=CH-R3af (wherein R3af represents a C02H4C02-Ci4^ group),

Rd4g& Re4g independently and independently represent a argon atom, a Ci.4 alkyl group, a C02H or a CCVCw alkyl group, and m4g represents an integer of 1 to 3, independently of each other. [8] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [3] to [6] wherein R3 is a group represented by the formula (4h):

Arm is a benzene ring or a pyridine ring, m4h, n4h' broad and one independently represent an integer of 〇~3 (where m4h+n4h+p4h+q4h is an integer of 〇~1〇; when, in the case of 1, M4h represents an integer of 2 or 3), and the remaining symbols are as defined in [4]. [9] A bicyclic pyrimidine compound such as [8] or a physiologically acceptable salt thereof, wherein

Ra4h is a hydrogen atom, a functional atom, or a CF3' c丨·6 alkyl group.丨6 alkoxy 161077.doc -22· 201245190 base,

Rb4h is not (vi) C02H, or (xi) C02CR3glR3g2R3g3 (here, R3gl, R3g2 and R3g3 each independently represent a hydrogen atom, or c, and the group can be made via 〇H, Cl ethoxy, 5 or 6 members) a saturated heterocyclic group or a substituted 'd C each independently represents a hydrogen atom or a Ci.4 courtyard)),

R d4h

R e4h

R

Rg '.h4h R·' RH, Rk4h are independently of each other and have a plurality of groups independently representing a nitrogen atom or a Cw alkyl group, or Rf4h and a ruler (10) may also be hard with the bond. 〇 妷 atom together form a cycloalkyl ring of 3 to 6 members, m4h is 1 or 2, 1141 > is an integer of 1 to 3, p4h, q4h, r4h and s4h are each independently 〇4l. In the case of 1, m4hg2). [10] The bicyclic μ compound according to any one of [8] or [9] or a physiologically acceptable salt thereof, wherein Rb4h is (xi) C02CR3glR3g2R3s3 (here, R3gl, R3g2 and W are as [9] Said in the definition of ]. Ask the bicyclic (4) of the term "(8)" in [8] to (10), where the Rb4h is 850.01.doc •23· 201245190 (xi) C02CR3glR3g2R383 (here, R3gl, RW and RW each independently represents a hydrogen atom or a Cw alkyl group (the group may be substituted by a hydrazine H or a C4 alkoxy group). [12] The bicyclic pyrimidine compound according to any one of [8] to [11] or A physiologically pharmaceutically acceptable salt, wherein R1 is a hydrogen atom or a functional atom, or a physiologically acceptable salt thereof, wherein R1 is a group represented by the following formula (2a,) or (2b,): [Chem. 15]

[in the formula,

Ra2a and Ra2b are each independently a hydrogen atom, a halogen atom, a Cw alkyl group or a Ci. 4 alkoxy group, and n2a and 11215 are 0. [14] The bicyclic pyrimidine compound according to any one of [3] to [12] Or a physiologically acceptable salt thereof, wherein R1 is a group represented by the following formula (2c,): [Chem. 16] Eight n2c

[in the formula, it can be arbitrary

Ra2e is a hydrogen atom or a fluorine atom (as long as it is chemically tolerable, it is substituted for a plurality of such groups), 161077.doc -24- 201245190 卩2. For 〇, !^ is an integer of i~4]. [15] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [3] to [12] wherein R1 is represented by the following formula (2d,) or (2gl):

[in the formula,

Ra2d and Ra2g are hydrogen atoms, X2d and X2g are oxygen atoms, 卩2 <1 and 114 are 1, 1112 (1 is an integer of 2 to 3, and 112 £1 is an integer of 〇~1). [16] as [3] The bismuth pyrimidine compound according to any one of [12] or a physiologically acceptable salt thereof, wherein R1 is lower, +. 4 μ, and ' horse is represented by the following formula (2e,) Base: [Chem. 18]

(2e·) [wherein, ^^ is an alkoxy group, and Rd2e and Re2e are each independently a hydrogen atom or a Cm alkyl group, and each of the plurality of groups is respectively set to be 161077.doc *25- 201245190 1126 An integer of 2 to 4]. The bicyclic pyrimidine compound or a physiologically acceptable salt thereof, wherein R2 is a group represented by the following formula (3c) or (3d): [Chem. 19] ]

(3c)

Wrn3d ^~Xyx3d

Ra3d M'n3d (3d) [wherein, each symbol is as defined in [4]]. [18] The bicyclic μ compound or a physiologically acceptable salt thereof according to any one of [3] to [17], wherein R2 is a group represented by the following formula (3e): [Chem. 20]

(3c) [wherein W is a hydrogen atom, and n3c is an integer of 4]. Π9] a bicyclic (iv) comonate such as [18] or a physiologically acceptable salt thereof, wherein the n3c is a bicyclic pyrimidine compound of 2 to 4» or the following formula (3a): Physiological [20] as [3] Salt tolerable to any of [16], wherein R2 is [Chem. 21]

-r-R838 [wherein, Ra3a is a hydrogen atom, or a C.6 alkoxy group 161077.doc -26-201245190 group substituted with a C alkoxy group, n3ag0], and X is an oxygen atom. [2] The bicyclic pyrimidine compound according to any one of [1] or [2] or a physiologically acceptable salt thereof, wherein R1 represents the following formulas (2a), (2b), (2c), (2d) , (2e), (2f), or (2g): [Chem. 22] > Ra2a J5~Ra2b (2b)

(4) Ra2n (2f) [wherein, β, Rm ' Ra2c, Ra2d, Rb2, Π Ra2g each independently represent a hydrogen atom, a dentate atom, CF3, CN, 〇H, Ci6, a Cw alkoxy, c, .6 alkylcarbonyl, c〇2Rla, NRlbR, c (, NRi w Ra2n represents a hydrogen atom, CF3, CN, C alkyl, CK6 alkylcarbonyl, CO2R ' ^RlbR, c^ C(=〇)NRldRle , RR And R, Rd, and Rle each independently represent a hydrogen atom, or a group of N, which may be bonded to each other: a cyclic amine group of 4 to 8 members is formed, and # represents an oxygen atom or a na, (wherein, RC2 represents an alkyl group) 'Aq-io and 28 represents an oxygen atom or a sulfur atom, : 2fl

(2g) (2θ)

Ra2f, Ra29 161077.doc -27· 201245190 n2e represents an integer of 1 to 6, m2d represents an integer of 1 to 3, n2d represents an integer of 0 to 3, n2e represents an integer of 0 to 8]; R2 represents the following formula (3a) Any one of (3b), (3c), (3d) or (3e): [Chem. 23]

^",...", ^", 尺山,尺(...) independently represent a hydrogen atom, a halogen atom, CF3, CN, OH, C "6 alkyl, fluorene:16 alkoxy, q 6 alkylcarbonyl, C02R2a' NR2bR2c or C(=〇)NR2dR2e, R2a, R2b, R2. R2d and R2e each independently represent a hydrogen atom or a halogen atom, or R2b and R2C, or RU and ye may be bonded to each other to form a cyclic amine group of 4 to 8 members, and X3d represents an oxygen atom or a sulfur atom. Or _N(Rc3)·(wherein, RC3 represents a sub or Ci-ioalkyl group), the original n3a represents an integer of 〇~6, n3b represents an integer of 〇~6, 161077.doc -28· 201245190 n3e represents 1~ An integer of 6, m3d represents an integer of 1 to 3, n3d represents an integer of 〇~3, n3e represents an integer of 0-8, and R3 represents the following formula (4a), (4b), (4c), (4d) or (4e): [24]

[in the formula,

Ra4a, Ra4b, 尺^ and Ra4d independently represent a hydrogen atom, a _ atom, a CF3, a CN, an OH, a Cuo alkyl group, a c3.6 cycloalkyl group, a Ci6 alkoxy group, a C3-6 cyclodecyloxy group, and Cu. Alkyl group, C02R3aa, NR3abR3ac, C(=0)NR3adR3ae or CH=CH-R3af (wherein R3aa, R3ab, R3ac, R and R each independently represent a hydrogen atom or a C^o group, or a ruler 331 And R3ae, or ruler---... can also form a cyclic amine group of 4 to 8 members with each bond; R3af represents CN, C02H, C02R3f丨 or c(=〇)NR3f2R3n, 161077.doc -29- 201245190 R, R and Rule 30 independently represent a hydrogen atom or a Ci-6 alkyl group, Rd4a^Re4a '

Rd4b^Re4b '

Rd4c ' R'c, Rf4>Rg4c,

Rd4d, Re4d, Rf4d and RW, and R 6 and Rg4e independently of each other or in the presence of a plurality of hydrogen atoms, OH, CN6 alkyl, C02H, CCVCm alkyl, C!·6 alkoxy, respectively. Or a phenyl group (here, the phenyl group may be substituted by a halogen atom, CF3, Cw alkyl group, c〇2H, C02-CU alkyl group or Ci-4 alkoxy group), or Rd4a and Re4a, Rd4b and Re4b , Rf4c and Rg4c, Rd4c^Re4d, Rf4d&Rg4d, and Rf4e&Rg4e may also form a 4 to 8 membered cycloalkyl ring together with the same carbon atom to which they are bonded, or 'bonding Two Rd", Rd4b, Rd4c, Rf4e, Rd4d, Rf4d or Rf4e on a carbon atom adjacent to each other through 0 to 3 carbon atoms may also be bonded to the 2 carbon atoms and the two carbon atoms bonded thereto The carbon chains together form a 4 to 8 membered cycloalkyl ring, and rMc and RMc^RMe each independently represent any of the following (1) to (xi): (1) a hydrogen atom, (ii) a dentate atom, (iii) OH, (iv) OR3M, (v) CN, (vi) C02H, 161077.doc -30- 201245190 (vii) C(=0)NR3b2R3b3, (viii) S02NR3b4R3b5, (ix) NR3eC(=0)NR3b6R3b7, ( Here, 'R3bl, R3b2, R3b3, R3b4, R3b5, R3b6, R3b7 and R3e each independently represent a ruthenium atom or a group, or R3b2 and R3b3, r3m and R3b5, or R3b6 and R3b7 may also be bonded to each other. Forming a cyclic amine group of 4 to 8 members), (X) any group represented by the following formula (4f): [Chem. 25]

(here, R34f represents a hydrogen atom or h, an alkyl group), or (xi) C02CR3glR3g2R3g3 (here, R3M, R3g2 and R... each independently represent a hydrogen atom, a C 1.4 alkyl group (the group may be subjected to Cl·) 4 alkoxy, C3 net, its glycine-T.3. 6 cycloalkyl (this group may be substituted by Ci4 alkoxy), 5 or 6 member saturated heterocyclic group, or old oxy group) c 3 - 1 0 ring-burning group has a saturated heterocyclic ring of 5 members or employees (the group may be substituted by 1 to 2 substituents selected from a fluorine atom and a C14 alkane hydrogen group 4, M. 4 condition rolling base) ), 161077.doc -31. 201245190 C6-l aryl (δ 玄 can be substituted by dentate atom or c6_1 () aryl (this group can be substituted by halogen atom or Cl-4 alkoxy)), 5 a saturated heterocyclic group of 6 or 6 members, or a heteroaryl group of 5 to 10 members (the group may be substituted by a Cw alkyl group or a C 4 alkoxy group), m, m, m and md* are independently represented An integer of 0 to 10, n4c, n4d, and n4e each independently represent an integer of 0 to 10]. [22] The bicyclic pyrimidine compound according to any one of [1], [2] or [21] or a physiologically acceptable salt thereof, wherein the γ is represented by the formula (π), (ΙΠ) or: 26] ^ again, cA R9 (HD (II) (V) [where the symbols are as defined in [1]] [23] such as [1], [2], [21] or [ A bicyclic pyrimidine compound or a physiologically permissible salt thereof, wherein Y is represented by the formula (III): [Chem. 27] Further (丨丨丨). [24] [21] to [ The bicyclic pyrimidine compound or a physiologically acceptable salt thereof, wherein R3 is represented by the formula (4a), (4b), (4c) or (4e) Table 161077.doc -32-201245190: [化28]

m and "1 b respectively represent integers from 0 to 8, respectively, m and , respectively, representing integers of 〇~1〇 (wherein below), I is ΐϋ, and the remaining symbols are as defined in [21] ]. The bicyclic (tetra) compound or a physiologically acceptable salt thereof, wherein R3 is represented by formula (4a) or (4b):

[in the formula,

R and R are independently hydrogen atoms, halogen atoms, CN, 16I077.doc •33- 201245190

Cj.6 alkyl, Cw alkoxy, c〇2H or CCVCw alkyl, «143 and 〇1415 are each independently an integer from 1 to 3, and the other symbols are as defined in [21]. [26] The bicyclic mouth bite compound of [25] or a physiologically acceptable salt thereof, wherein Ra4a and Ra4b are each independently a hydrogen atom, a hydrazine H or a cN4 alkoxy group, and 11143 and m4b are each independently 1 Or an integer of 2. [27] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [21] to [24] wherein R3 is represented by the formula (4c):

[wherein, m4c and n4e each independently represent an integer of 0 to 6 (where Wn is "1" or less), and the remaining symbols are as defined in [21]] [28] as in [27] a bicyclic whistling compound or a physiologically acceptable salt thereof, wherein 1134 <: is a hydrogen atom, a halogen atom, hydrazine H, C 丨.6 alkyl, c 丨.6 alkoxy, CC^H^CCVCw alkyl ,

Rb4c is (v) CN, 161077.doc • 34· 201245190 (vi) C〇2H ' (vii) C(=〇)NR3b2R3b3, (x) Any of the following formulas (4〇: [化31 ]

(Herein, R34f is as defined in [21] (xi) C02CR3g, R3g2R3g3 (here, R3gl, R3g2 and R3g3), or independently hydrogenogen

Rd4c, Re4c, R(4) and Rg4c are each a hydrogen atom, and the claw "is an integer of 1 or 2, and 114" is an integer of 1 to 3. [29] A bicyclic pyrimidine compound as described in [28] or its physiologically permissible Scale

Ra4e is a hydrogen atom,

Rb4cS (vi) C02H, (x) Any of the groups represented by the following formula (4f): [Chem. 32] 161077.doc -35- 201245190 〇 〇 〇 9 "

An^h^n^cn An,so2r^ ^'〇H NHz ϋ4 4 <4° (here, R34f is as defined in [21]) 5 (xii) C02R3g4 j-decay ° bite compound Or its physiological formula (2a), (2b) or (2g) means: (here, the ruler is 匸丨·*alkyl). [30] The salt permissible according to any one of [21] to [29], wherein Ri is as follows [Chem. 33]

(2a) (2b) (2g) [wherein, each symbol is as defined in [21]]. [3] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [21] to [3], wherein R1 is represented by the following formula (2a): [Chem. 34]

[In the formula, Ra2a is as defined in [21]]. [32] The bicyclic bite compound of [3 1] wherein R 2a is a hydrogen atom, a dentate atom, c〇2h or a CCVCw alkyl group, or a physiologically acceptable salt thereof. [3] The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of [21] to [3, wherein R2 is represented by the following formula (3 magic or (3 (1): I61077. Doc • 36 - 201245190 [化35]

[wherein, each symbol is as defined in [21]]. [34] The bicyclic bite compound of any one of [21] to [33] or a physiologically acceptable salt thereof, wherein the towel is represented by the following formula (3e): [Chem. 36]

(3c) [In the formula, Ra3c is a hydrogen atom, an integer of η3〇Αι~4]. [35] A bicyclic pyrimidine compound according to [34] or a physiologically acceptable salt thereof, wherein 11 is 4. [36] The bicyclic cardiotonic compound of any one of [1] to [35] or a physiologically acceptable salt thereof, wherein hydrazine is a sulfur atom or -n(r6)· (here, R6 represents a hydrogen atom) Or C 1.4 base). [37] A bicyclic compound according to [36] or a physiologically acceptable salt thereof, wherein X is -NH-. [38] A bicyclic mouth bite compound according to [36] or a physiologically acceptable salt thereof, wherein X is a sulfur atom. [39] The bicyclicity of any of [1] to [38], a biting compound or a physiologically acceptable salt thereof, wherein r1r5 is a hydrogen atom. The bicyclic pyrimidine compound or a physiologically acceptable salt thereof, wherein the above bicyclic pyrimidine compound is selected from the group consisting of: {4-K3-U2-(ring); Hexyl thiol) _4_ oxo_3_phenyl _3,5,7,8_tetrahydro ton bite [4,3-d] bite ·6 (4 Η)·yl] aryl} aza Cyclobutanyl)methyl]phenyl}acetate methyl ester (Example 59), y)-3-{4-[(3-{[2-(cyclohexylsulfanyl)_4_oxo_3 _Phenyl_3,5,7,8_ tetrahydroindeno[4,3-d]〇^-6(4H)·yl]yl}}azetidinyl·i))-methyl]ben } 丙 丙 稀 稀 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨 旨·6(4Η)-yl]carbonyl}azetidinyl-fluorenyl)indolyl]ethyl)acetate ethyl ester (Example 77), 4-(3·{[2-(cyclohexyl) Thioalkyl)-4-oxo_3_phenyl_3 5 7,8 tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidine_丨_ Ethyl butyrate (Example 81), 4-[2-(3-{[2-(cyclohexylsulfanyl)-4-oxo-3)phenyl_3,5,7,8_ Tetrahydroindolepyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl-indoleyl) Benzyl benzoate (Example 79), 3-{4-[(3-{[2-(cyclohexylthioalkyl)-4-oxo-3-phenyl)-3,5,7,8 Tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl-mercapto)methyl]-phenyl}propionic acid methyl ester (Example 78), . 3-{4-[(3-{[2-(cyclohexylamino)-4-oxo_3_phenyl_3 5 7 8 tetrahydroindolepyridinium [4,3-d]pyrimidine-6 (4H)-yl]carbonyl}azetidinyl-indole-methyl)phenyl]propionate methyl ester (Example 21), 6-(3-{[2-(cyclohexylthioalkyl) -4·oxo·3_phenyl_3,5,7,8_tetrahydro.Bit 161077.doc -38- 201245190 and [4,3♦ dense bite_6(4H)_yl] Azetidinated small base) ethyl hexanoic acid vinegar (Example 82), 4-[2-(3-{[2-(cyclohexylamino) oxooxy-3) _3,5,7 , 8_tetrahydro π ratio bite [4,3-d] 〇^_6(4H)-yl] aryl}azetidinium + yl)ethyl]benzoic acid methyl ester (Example 24), 3 -{4-[(3-{[2·(cyclohexylsulfanyl)-4)oxophenyl_3,5,7,8_tetrahydroindeno[4,3-d](tetra)-6( 4Η)·基基基基}azetidinyl)methyl] phenyl}ethyl propionate (Example 65), 9-(3-{[2-(cyclohexylwei)-4_ Oxygen-based _3,5,7,8_tetrahydrogen And biting [4,3-d].密6_4(4Η)·基基的基基}azetidinyl acetonide) 壬 酉 ( (Example 83), {3-[(3-{[2-(cyclohexylthio))_4 -oxo 3phenyl_3,5 7,8 tetrahydroanthraquinone and [4,3-d] mouth bite _6(4H)-yl]yl}}azetidinyl"methyl)benzene Ethyl acetate (Example 118), {3-[(3-{[2-(cyclopentylsulfanyl))-4_oxophenyl]3,5,7,8_tetragen. And [4,3-d] mouth biting _6(4H)-yl]yl}N-heterocyclic calcinin+yl)methyl]phenyl}acetate methyl ester (Example 119), {3-[(3 -{[2-(cyclohexylthioalkyl)_3_(3,3_: a $ & pH 3,5,7,8-tetrahydrogen. Bite and [4,3_d] mouth bite.6(4Η) Ethyl m-based azetidin-1-yl)methyl]phenyl}acetic acid decyl ester (Example 107), ^ Μ-[(3·{[2-(cyclopentylwei))_4_ Oxygen·3_phenyl_3,5,7 bite at the end of the winter and [4,3-d] mouth bite·6(4Η)·yl]yl} azetidinyl)methyl] stupid Ethyl acetate (Example 151), ^ 3-{4·[(3-{[2-(cyclohexylthioalkyl)-4-oxophenyl-3,5,7,8-tetra 161077.doc -39- 201245190 Pyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidinyl-indoleyl)methyl]_ 2 -phenylene}propionic acid Vinegar Example 97), {4-[2-(3-{[2-(cyclohexylthioalkyl)-4-oxo-3•phenyl_3,5,7,8-tetrahydropyrido[4] , 3-d]pyrimidin-6(4H)-yl]carbonyl}azetidinyl-indenyl)ethyl]phenyl}ethyl acetate (Example 98), {4-[(3-{[2 -(cyclohexylsulfanyl)-4.oxophenyl_3 5 7 8 tetrahydroindolepyrido[4,3-d]pyrimidin-6(4Η)·yl]carbonyl}azetidine_丨_yl)methyl]phenoxy}acetate (Example 100), {3-[(3-{[2-(cyclohexylsulfanyl))_4_oxophenyl]3 5,7 8 Tetrahydropyridinium pyridine[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl"yl)indolyl]phenoxy}acetate (Example 1 〇1), {4-[(3_{[2-(cyclohexylsulfanyl)_3_(3,3-difluorocyclobutyl)) oxo- 3,5,7,8-tetrazine. 3♦ 唆6·6(4Η)_yl] aryl}azetidin-1-yl)indolyl]phenyl}acetic acid decyl ester (Example j25), {4-[(3-{[2 ·(cyclohexylthioalkyl)_3_(3,3-difluorocyclobutyl)_4_oxo 3'5'7'8-tetrahydroton bite [4,3__biting_6(4Η)_ base Alkyl}azetidin-1-yl)methyl]benoxy}acetic acid ethyl acetate (Example 114), 3-{4-[(3-{[2-(cyclopentylsulfanyl) ) 4_oxophenyl·3,5,7,8-tetraazolo[4,3-d]^6(4Η)-yl]yl}Nylidene small))^ Benzene Ethyl propionate (Example 152), soil {4-[(3-{[2·(cyclopentylsulfanyl)-4)oxo+phenyl_3,5,7,8-^ pyridine [4,3-d] pyridine-6(4Η)-yl]alkyl}azetidinyl)methylpentanoate ethyl acetate (Example 120), {4-[(3- {[2·(cyclobutylsulfanyl)_4•oxo-3phenyl-3 5 7 winter four gas. 161077.doc -40. 201245190 Acridine [4,3_d]pyrimidin-6(4H)-yl]carbonylindole-butane-indenyl)methyl]phenyl}acetic acid (Example 1 5 3), 1-{4-[(3-{[2-(cyclohexylsulfanyl)_4_oxo_3_styl]3,5,7,8-tetrahydropyrido[4,3- d]pyrimidine_6(4H)-yl]carbonyl}azetidinyl]indenyl]phenyl}cyclopropane decanoate (Example 99), {4-[(3-{[2- (cyclohexylsulfanyl)_4-oxo_3_(11-pyridyl_3_yl)_3,5,78-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}Nitrogen Heterocyclobutanemethyl]phenyl}acetic acid decyl ester (Example 130), cyclohexylsulfanyl)_4.oxo_3_stupyl_3 5,7 8 tetrahydropyrido[4,3-d Pyrimidine-6(4H)-yl]carbonyl}azetidinium-yl)methyl]pyridin-2-yl}oxy)acetic acid decyl ester (Examples 1〇3), {4-[( 3-{[2-(cyclohexylsulfanyl)·4-oxo_3_[tetrahydrofuro-2-ylmethyl]_ 3,5,7,8-tetrahydropyrido[4,3-d Pyrimidine-6(4H)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}acetic acid (+/-)-branched (Example 129), {4-[(3- {[2-(Cyclohexylsulfanyl)-4-oxo_3_[(2R)_tetrahydroanthracene-2-ylmethyl]-3,5,7,8-tetrahydro) Pyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidin-1 -yl)methyl]phenyl}acetic acid decyl ester (Example 135), Η-[(3) ·{[2-(cyclohexylsulfanyl)-4•oxo_3_[(2S)_tetrahydrofuran·2_ylindenyl]-3,5,7,8-tetrahydro" And [4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}acetic acid decyl ester (Example 137), 3-{4-[ (3-{[2-(cyclohexylsulfanyl)-4-oxo-3-3-phenyl_3,5,7,8-tetrazide-pyrido[4,3-d]pyrimidine-6 ( 4H)-yl]carbonyl}azetidinyl-yl)methyl] phenyl}propionic acid 2·methoxyethyl ester (Example 203), 3-{4_[(3-{[2- (cyclohexylsulfanyl)-4-deutero_3_stupyl_3,5,7,8>_tetrahydro 161077.doc -41 - 201245190 Pyrido[4'3-d]pyrimidine-6 (4H )]]]carbonyl]azetidinyl)methyl]phenyl}propionic acid 2-hydroxyethyl ester (Example 2〇4), {4-[(3-{[2-(cyclohexylsulfuric) Alkyl)_3_(furan-2-ylindenyl)-4_oxo-3,5'7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidine Methyl-1-yl) decyl]phenyl}acetate (Example 139), {4-[(3-{[2-(cyclohexylsulfanyl))-3(2• methoxyethyl) 4_oxo·3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidin-1-yl)indenyl]phenyl}acetic acid Methyl ester (Example 14A), 6-(3-{[2-(cyclohexylsulfanyl)-4-oxophenyl-3,5,7,8-tetrahydro. Bis-[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl) decanoate (Example 105), 4-[(3-{[2-(cyclo) Hexylsulfanyl)_4_oxo-3-phenyl-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidine Ethyl hydrazide benzoate (Example 123), {4-[2-(3-{[2-(cyclohexylsulfanyl)-4)oxo_3_phenyl_3,57 , 8_tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidinyl "yl)ethoxy]phenyl}acetic acid decyl ester (Example 102), (+/-)- {4-[(3 -{[2-(cyclohexylsulfanyl)-4-oxo-3-(tetrahydrofurfuryl)-3-ylindolyl)-3,5,7 , 8-tetrahydro. Bipyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidin-1-yl)indenyl]phenyl}.methyl acetate (Example丨46), {4-[(3-{[2-(cyclohexylthioalkyl)-4-oxo_3_[(2 ft)_tetrahydrofuran-2-ylmethyl]-3,5,7, 8-tetrahydropyrido[4,3-(1]pyrimidine>_6(4;^1)-yl]carbonyl}azetidin-1 -yl)methyl]phenoxy}acetate ( Example 丨丨7), 3-{4-[(3-{[2-(cyclohexylsulfanyl)-4-oxo_3_[(211)_tetrahydrofuran 2_ I61077.doc • 42· 201245190) Base]-3,5, 7,8-tetrahydro.pyridinium[4,3-(1]pyrimidin-6(411)-yl]carbonyl}azetidin-1-yl)indolyl]phenyl}propionate ethyl ester ( Example 丨49), {4-[(3-{[2·(3-Butoxyphenoxy)_4_oxo·3_phenyl_3 5 7,8_tetrahydrogen ratio bite and [ 4,3-(1)-dip-6(411)-yl]carbonyl}azetidin-1-yl)methyl]phenoxy}acetate (Example 214), {4-[( 3-{[2-(3-butoxyphenoxy)_4_oxo_3_phenyl_3 5 7 8 tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl] Carbonyl}azetidinylindole-yl)methyl]phenyl}acetate methyl ester (Example 95), and {4-[(3-{[2-(cyclohexylsulfanyl))_3_[(2R) _2_methoxypropyl]-4 oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(411)-yl]carbonyl}azetidin-1- Methyl]methyl] phenyl} methyl acetate (Example 150) [41] A bicyclic pyrimidine compound represented by the formula (Ib) or a chemically stable salt thereof: [Chem. 37]

Wherein P is a protecting group for an amine group, and represents a fluorenyl group substituted with 1 to 3 phenyl groups (the phenyl group may be substituted with an oxime group of oxime~) or (: 4) alkoxy group. (c = 〇) 〇 Rpi, or (C = 0) RP2, R represents a Cl 4 alkyl group (the group may be substituted by 1 to 3 halogen atoms, wherein, when the 4 group is a methyl group, Substituted by 1~3 i-atoms, phenyl or 9-fluorenyl) or (:]-4 alkenyl, 161077.doc •43· 201245190

Rp2 represents a hydrogen atom, a Cw alkyl group (this group may be taken through 1 to 3 halogen atoms by ^3 nitrite atoms), wherein when the group is a Ci 2 alkyl group, a sub, or a Cl 4 is a substituted oxy group) or a phenyl group, and R1, R2, R4, R5 and X are as defined in [4]. [42] A method for producing a bicyclic pyrimidine compound represented by the formula (Id) or a physiologically acceptable salt thereof, which comprises the following two steps: a bicyclic pyrimidine represented by the formula (Ib) as defined in [41] a compound or a chemically stable salt thereof: [Chem. 38]

Deprotection, obtaining a bicyclic pyrimidine compound represented by the formula (Ic) or a chemically stable salt thereof: [Chem. 39]

Then, it is reacted with a compound represented by the formula (Via): R3 - L (Via); [Chem. 41] 161077.doc 201245190

Wherein L is a leaving group and represents a halogen atom or 〇s〇2rL; wherein rl represents a Cw alkyl group which may be substituted by a fluorine atom or a phenyl group which may be substituted by a Cw alkyl group, and P2 is as [41 As indicated by the definition in [ ], R, R2, R3, R4, R5 and X are as defined in [4]. [43] A method for producing a bicyclic pyrimidine compound represented by the formula (le) or a physiologically acceptable salt thereof, which comprises the following two steps: a bicyclic pyrimidine represented by the formula (ib) as in [41] a compound or a chemically stable salt thereof: [Chem. 42]

Deprotection, obtaining a bicyclic pyrimidine compound represented by the formula (Ic) or a chemically stable salt thereof: [Chem. 43]

Then, it is combined with the compound represented by the formula (VIb): [Chem. 44] 161077.doc -45· 201245190 R3爻 y=0 (vib) p3p2 is reacted;

[wherein, R3pl represents a group represented by any one of the following formulas (4gp), (4hp) or (4ip): [Chem. 46]

Ra4h

M4hp and m4ip each independently represent an integer of 0 to 4 (wherein, in the case where r4h is 1, m4hp represents an integer of 1 to 4; in the case of 3 to 1, m4ip represents an integer of 1 to 4), 161077 .doc -46- 201245190 R3p2 represents a hydrogen atom or a Cu alkyl group, P2 is as defined in [41], Rb4i, 'Rj4h,

Rl, R2, R4, R5, x, Arm, rose a4g, Ra4h, Rb4h

Rd4g, Re4g, Rd4h, Re4h, Rf4h, Rg4h, fh, r4h, s4h

Rk4h, Rd4i, Re4i, Rf4i, Rg4i, n4h h 4h 4. P, π, n, and s41 are as defined in [4]. [44] A substituted azetidinium compound represented by the formula (VII) or a chemically stable salt thereof: [Chem. 47]

[in the formula,

Rb4h represents CChCRWRWR, where R3g 丨, R3g2 and R3g3 each independently represent a hydrogen atom, or a CM alkyl group (the group may be substituted by hydrazine H or an alkoxy group), Rg4h, Rh4h, Ri4h, Rj4h, s , R and R5 are as defined in [4]

Arm, Ra4h, Rd4h, Re4h, Rf4h Rk4h, m4h, n4h, p4h, q4h, f4h, meaning). [45] A method for producing a bicyclic pyrimidine compound represented by the formula (If) or a physiologically acceptable salt thereof, which comprises the following steps: 161077.doc • 47· 201245190 Let the formula [44] (VII) a substituted azetidine compound or a chemically stable salt thereof: [Chem. 48]

And a bicyclic pyrimidine compound represented by the formula (VIII) or a chemically stable salt thereof: [Chem. 49]

(VIII)

R1 , R2 [where,

Rb4h is as defined in [44],

Arm, Ra4h, Rd4h, Re4h, Rf4h, RMh, Rh4h, Ri4h, Rj4h, I6l077.doc •48· 201245190

4h, p4h, q4h, r4h, and s4h, and R1, R2, R4, R, and X are as defined in [4]. [46] A pharmaceutical composition comprising a bicyclic pyrimidine compound according to any one of [[] to [4] or [49] or a physiologically acceptable salt thereof. [47] A prophylactic and/or therapeutic agent for a disease of MGAT, which is a bicyclic pyrimidine compound according to any one of [1] to [40] or [49] or a physiologically acceptable salt thereof. Active ingredients. [48] An obesity, metabolic syndrome, hyperlipidemia, hyperlipidemia, 咼VLDL (very i〇w_density lip〇pr〇tein, ultra-low-density lipoprotein), hyper-fatty acidemia, diabetes Or a preventive agent for atherosclerosis and/or a therapeutic agent, which is effective as a bicyclic pyrimidine compound according to any one of [1] to [4] or [49] or a physiologically acceptable salt thereof. ingredient. [49] The bicyclic pyrimidine compound according to [4] or a physiologically acceptable salt thereof, wherein R1 is the following formula (2a·) or (2b·): [Chem. 51]

[wherein, _ atom, Cm alkyl or

Ra2a&Ra2b are independently hydrogen atoms

Cl-4 alkoxy, n2a & 11213 is 0], the following formula (2c·): [Chem. 52] 161077.doc -49- 201245190

[in the formula,

Ra2c is a hydrogen atom or a fluorine atom (as long as it is chemically tolerable 'Bei 1J can substitute a plurality of such groups at any position), p2c is 0, 112 £: an integer of 1 to 4, or the following formula (2d) '): [53]

(2d1) [where,

Ra2d is a hydrogen atom, X2d is an oxygen atom, p2d$, 1 > 1112 (1 is an integer of 2 to 3, and n2d is an integer of 0 to 1); R2 is a formula (3c): 54]

161077.doc -50- 201245190 [wherein Ra3c is a hydrogen atom 'n3c is an integer of 2 to 4); R3 is a formula (4h): [Chem. 55]

Arm is a benzene ring or a oxime ring, alkyl or Cw alkoxy

Ra4h is a hydrogen atom, a halogen atom, a base,

Rb4h is (xi) C02CR38, R3g2R3g3 (here, R3gl, RW and RW each independently represent a hydrogen atom, or

Cl·4 alkoxy, 5- or 6-membered saturated R and R3b9 independently represent hydrogenogen

Ci-4 alkyl (the group may be substituted by OH, a cyclic group or NR3b8R3b9, a sub or Cw alkyl group),

Rd4h, Re4h, Rf4h, Rg4h, Rh4h, Ri4h, Rj4^Rk4h are independently of each other and have a plurality of groups independently representing a nitrogen atom or a hydrazine "alkyl group, or Rf4h and Rg4h may also be bonded to the bond. The broken atom of the knot together forms a cycloalkyl ring of 3 to 6 members, 16I077.doc •51 · 201245190 m4h is 1 or 2, and η is an integer of 1 to 3, P4h, q4h, and s4h are independently 〇 or J, respectively. (wherein, in the case where 1 is 1, m4h is 2)]; R and R5 are each a hydrogen atom, X is a sulfur atom or -NH-, and y is a formula (in): [Chem. 56]

(III) The basis of nothing. [Effects of the Invention] The bicyclic pyrimidine derivative of the present invention and a physiologically acceptable salt thereof have a metabolic syndrome, a high-fat gold MGAT inhibitory action, and can be used as an obesity, a disease, a serotonemia, a high VLDL. Prophylactic and/or therapeutic agents for hyperemia, hyper-fatty acidemia, diabetes, and atherosclerosis. [Embodiment] Hereinafter, the terms used in the present specification will be described. The "burning base" and the "burning base" are, for example, a straight or branched alkyl group having a carbon number of one to one (also referred to as "Cuo" in the present specification), and specific examples thereof include: Dibutyl, decyl, ethyl, propyl, isopropyl, butyl, isobutylbutanyl, pentyl, isopentyl, third amyl, 161077.doc •52· 201245190 base, dissident Base, octyl, sulfhydryl, sulfhydryl and the like. Preferably, R1, R2, R4 and R5 have a carbon number of 1 to 6 (also referred to as "Ci6" in the present specification), and a carbon number of 1 to 10 (c)_10 in R3. More preferably, it is carbon number in R3! ～6 (C!·6) » As preferred examples, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, t-butyl, A pentyl group, an isopentyl group, a third amyl group, a hexyl group and the like. The lower-grade alkyl group and the "low-grade alkyl group" represent a linear or branched alkyl group having a carbon number of ～8 (also referred to as "Cl_8" in the present specification), and specific examples thereof include a methyl group. Ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, pentyl, isopentyl 'tripentyl, hexyl, isohexyl, octyl and the like. Preferably, the number of carbon atoms in R1, R2, R4 and R5 is from 1 to 6 (Cl·6)', and the number of carbon atoms in R3 is from 1 to 8 (Cw). More preferably, the carbon number in the ruler 3 is 1 to 6 (C!.6). Further, it is preferably one to four carbon atoms in R1, R2, R3, R4 and R (also referred to as "Ci4" in the present specification). Preferred examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a second butyl group, a third butyl group, a pentyl group, an isopentyl group, and a third pentyl group. , hexyl and so on. The "base group" and "dilute base" portions indicate, for example, at least 1 of the carbon-carbon single bonds of the "alkyl group" having 2 to 1 carbon atoms (also referred to as "2.1〇" in the present specification). A carbon-carbon single bond is changed to a carbon chain after a double bond, and as a specific example, a vinyl group, a propyl group, a 3-butyl group, an isobutyl group, a pentenyl group, and an 8-decene group are mentioned. Base, heptadienyl, 2,4,7-nontrienyl and the like. Preferably, it is 2 to 6 carbon atoms in R ' R2, R4 & R5 (also referred to as "C2·6" in the present specification), and 3 to 1 carbon in the rule 3 (this specification) Zhongyi Table 161077.doc •53- 201245190 is described as “C3-〗〇”). Specific preferred examples thereof include a vinyl group, an isobutyl group 1'4. a heptyl group and an anthracene group. The lower alkenyl group and the "lower base group" indicate that the carbon number is from 2 to 8 (the "lower alkyl group" which is also expressed as "C"" in the month). At least one carbon-carbon single bond is changed to a carbon chain after a double bond, and specific examples thereof include an ethylene group, a dilute propyl group, a 3 butyl group, and an isobutyl group 1,4heptanyl group. Preferably, the carbon number is 2 to 6 (C2.6) in R丨, R2, 4 and r5, and the carbon number is 2 to (4) I). t < 圭 is a carbon number of 3 to 6 in r3 (also referred to as "'" in this specification). Preferred examples thereof include a vinyl group, an isobutenyl group, and an Mheptadienyl group. The alkynyl group and the "alkynyl group" represent a carbon bond in which at least one carbon-carbon single bond of the carbon-carbon single bond of the "alkyl group" having two carbon atoms is changed to a triple bond. For example, an ethyl group, a propyl group, a 2-butynyl group, a 3-butynyl group, a 4-heptynyl group, a 3-hexynyl group, a 2,4-octadiynyl group, and the like can be mentioned. Preferably, Ri, R2, Μ and the carbon number are 2 to 6 ((: 2 6), and the second R 3 is 2 to 10 carbon atoms ((: 2-1 〇). More preferably In the rule 3, the number of carbon atoms is 3 to 6 (<:3·6). Preferred examples thereof include an ethynyl group, a propargyl group, a 2-butynyl group, a 3-butynyl group and the like. The alkynyl group and the "lower alkynyl group" indicate that at least one carbon-carbon single bond of the carbon-carbon single bond of the "lower alkyl group" having two to eight (C2-8) carbon atoms is changed to Specific examples of the carbon chain after the triple bond include an ethynyl group, a propargyl group, a 2-butynyl group, a 3-butynyl group, a 4-heptynyl group, etc., preferably R1, R2, and R4. In R5, there are 2 to 6 carbon atoms (ay, 2 to 8 carbon atoms in R3 (C2.8), and more preferably 3 to 6 carbon atoms in R3 ((:3·6) Preferable examples of 161077.doc -54· 201245190 include ethynyl group, propargyl group, 2·butynyl group, and butyl group. The "lower cyclic alkyl group" and "lower cycloalkyl group" are represented. A cyclic alkyl group having 3 to 8 carbon atoms (also referred to as "Cw" in the present specification), and specific examples thereof include a cyclopropyl group. Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Preferably, the number of carbon atoms is 5 to 7 (also referred to as Γ Cs_7 in the present specification). Preferably, it is within the ruler 2. The carbon number is 3 to 6 (Cw), more preferably 5 or 6 carbon atoms (also referred to as "CM" in the present specification). Preferred examples thereof include a cyclopentyl group and a cyclohexyl group. Cycloheptyl group, etc. The "lower cycloalkenyl group" and "lower cycloalkenyl group" represent a carbon-carbon single bond of a "lower cycloalkyl group" having 3 to 8 carbon atoms (C3.8). A carbon chain in which one or two carbon-carbon single bonds are changed to a double bond, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. And cyclooctenyl group. Preferably, the number of carbon atoms is 5 or 6 ((^·6). Preferred examples thereof include a cyclopentenyl group, a cyclohexenyl group and the like. The "lower alkoxy group" represents a linear or branched alkoxy group having from 1 to 8 (Cm) carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, and a propoxy group. Isopropoxy, butoxy, isobutoxy a second butoxy group, a third butoxy group, etc. Preferably, the number of carbon atoms is from 1 to 6 (Cw) in R丨, r2, ... and R5, and from 1 to 8 in R3. (Ci 8). More preferably, it is carbon number in R3! ~6 ((:| y. Further preferably, carbon number in R2, R3, R4 and R5) ~ 4 (C| 4) "Lower alkylthio group" means a group obtained by bonding a sulfur atom to a bonding group of a straight chain or an alkyl group having a carbon number of ～8 ((1:8), for example, a chain.

I歹J 161077.doc •55· 201245190 曱: thiol, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, second butylthio, tert-butylthio, etc. . Preferably, it is pure, ruthenium, and R5 is carbon (8) ~ 6 (Cl. 6), and pure 3 is carbon ^ ~ 8 hearts). More 2 good light R3 inside the carbon number 1 ~ 6 hearts). Further, it is preferable that the number of carbon atoms in R1, R, R, R4 and R5 is ~4 ((:14). : "The fangs atom" means a gas atom, a gas atom, a desert atom or a dish as R Preferably, the substituent in the group 3 is a gas atom and a chlorine atom is more preferably a fluorine atom. The "cyclic amine group" and the "cyclic amine group" portion indicate that at least one nitrogen is contained: oxygen may also be contained. A ring of 4 or 4 membered rings of an atom or a sulfur atom contains at least one nitrogen atom, and may also contain an oxygen atom or a cyclic amine group of a 4-membered ring to a 7-membered ring of a benzene ring. For example, azapinidine AF is a recombination (tetra) group, a ketone group, a imiline group, a "L /, a gas azacycloheptenyl group, a tetrahydroindenyl group, a tetrahydroisoquinoyl group, an anthracene哚基,异吲哚,, well, wood, 1-oxoisoindolyl, isodecyl, etc. It is better to list 昌Schang + oxime _, which can be cited as a better ratio a pyridyl group, a piperidinyl group, a porphyrin group, etc. '"Low-grade broth base" and "Low-grade broth base" part of the table dry key or "P-knife not carbon number 1 ~ 8 times Branched alkane group, as a specific example, 醯, Ethyl group, (4) J歹J, Methyl ethyl ketone, etc. It is preferred that J Isobutyl, aryl, and Sanjia can be listed as having a carbon number of ~6 (CI6). 1 ~ 4 (c^4) 〇 Better for "Fangji" and factory · « Double-ring or three-ring type: Minutes for 6-member ring ~ 14-member ring, Fang-style Fang Hydrocarbon (also referred to in the specification as ^c6i4 J61077.doc • 56· 201245190 aryl)), preferably a monocyclic, bicyclic or bicyclic aromatic hydrocarbon having a 6-membered ring to a 10-membered ring (this In the specification, it is also referred to as "c6 ionic aryl group". Specific examples thereof include a phenyl group, a naphthyl group, a phenanthryl group, a fluorenyl group and the like. Preferred examples thereof include a phenyl group, a fluorene-naphthyl group, and a 2-naphthyl group. And more preferably, it is a phenyl group. The "benzene ring" which is a preferred aspect of one of the formulas in the formulas (4g) and (4h) is represented by a substituent or a substituent, as described in the formula. Two may also be substituted with benzene at any position where substitution may be made via an oxygen-extension alkyl side chain. In the case where two of the extended-burning side-bonds are present in the formula (4h), Am represents a phenyl group. Bonding position of two side chains It may be any of the adjacent (〇) bits (1 '2 bits), the (m) bits (1, 3 bits), or the (P) bits (1, 4 bits), preferably the meta ( 1,3 digits) or para (1,4 digits), more preferably para (I 〆). The heteroaryl group and the "heteroaryl" moiety are selected to be selected from oxygen atoms, sulfur 2 = and nitrogen atoms. A monocyclic or bicyclic aromatic heterocyclic group of 4 to 10 members of one to four hetero atoms. Specific examples, examples #: base, fur. Nanji (furany) fuiTl , thiophenyl, hydrazino oxadiazolyl, anthracene, succinyl, hydrazone, iso-n-septyl, oxime-based, aziridine, azaindole, imidazolyl, isoxazolyl , triazolyl, thiadiazolyl, pyridylpyridinyl, sulfonyl ... morphyl, fluorene, isoindolyl, benzoindole, (d) and ett silk, (d) and (d) base, (d) (4) The base, the stiletto, the benzoic acid, the benzoxanthyl group, the benzohexanyl group, and the benzophenone are basically scented with a sulphur group and a benzoheptylene group. It is preferably a 5-membered ring or a 6-membered monocyclic aromatic heterocyclic group. Preferred examples of the compound include furfuryl, thienyl, carbazolyl, fluorenyl 161077.doc • 57- 201245190 oxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyridyl An azole group, a pyridyl group, a mouth bite group, a sorghum base, and the like. More preferable specific examples include a pyridyl group, a furanyl group (fUranyl, furyl), a thienyl group and the like. Preferably, it is a pyrrolyl group, a furanyh furyl group, a thienyl group and a pyridyl group in R1. More preferably, it is tlfyl (fUranyl, furyl) and in R. Than the base. It is disclosed that Arm in the formulas (4g) and (4h) respectively represent a 5- to 10-membered monocyclic or bicyclic ring containing a selected ~4$ hetero atom selected from an oxygen atom, a sulfur atom and a nitrogen atom. An aromatic heterocyclic ring, the name of which is substituted by a substituent, as described in the formula, may be substituted by an alkyl chain of oxygen and may be substituted with an unsaturated group which may be substituted. ring. Specific examples include, for example, indolo, thiophene, thiophene, oxazole, diazole, thiazole, thiadiazole, isothiazole, and oxadiazole. Sitting 'three saliva, sigh two. Sit, call: and I:, 嗒耕, °", quinoline, isoquinoline, benzothiazepine, phos, (4) and _, (4) and (four), ^, benzodiazepine, phenanthrene, benzo Mf f ring. Compared to the military ring aromatic heterocycle. As a preferred specific example, saliva, dissident saliva, ° sputum, and material 1 are two. Sitting, thiophene. Sit and squat. Sit, "by comparison. Sit, (four), D than bite n answer 5 . More preferably, it is 5 or 6 members of a single or a hetero atom having only 1 or 2 nitrogen atoms as a heterocyclic ring. As a better example of Zhao, the staff is not sitting, pyridine, the best can be listed as % saliva and _ ring, the best is _ ring. Compared with the "Zifang Fan iS2, . 幻中,, as described in the formula (4h), there are I6I077.doc -58-201245190 or more, but also through the oxygen alkyl group side chain, as long as chemically It can be tolerated that the bonding position of the side chains can be any of the bondable configurations. For example, when Arm is "(4) ring" < In case, 'Ar is replaced by the side chain described in the formula Can replace any position on the atom. Compared with the bite ring, when there are two alkyl side chains which can also be extended via oxygen as described in the formula (4h), the bonding sites of the two side chains are selected from the 2nd position of the pyridine ring other than the nitrogen atom. Any two positions of 6 bits t, preferably 2, 4 bits, 3, 5 bits, 4, 6 bits '2, 5 bits or 3, 6 bits, more preferably 2, 5 bits or 3, 6 bits. The "heterocyclic group" and the "heterocyclic ring" represent a monocyclic, bicyclic or tricyclic ring of 3 to 12 members containing one to four hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom. A saturated or unsaturated heterocyclic group. Specific examples thereof include pyrrolyl, furany, furyl, thienyl, oxazolyl, oxadiazole, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl and anthracenyl. Sulfhydryl, azaindole, imidazolyl, isoxazolyl, trisalyl, thiadiazolyl, pyridyl, pyrimidinyl, hydrazine, pyridinyl, quinolinyl, isoindolyl, stupid And 嗟 基 嗟, 嗟 并 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Thienyl, benzimidazolyl, benzoxazolyl, oxetanyl, azetidinyl, "•", each bite group, tetrahydrocarbamate, dioxolane, piperidinyl , piperene, high piperage, tetrahydropyranyl, thiocyclohexyl, benzophenanyl, thio-terinyl, cyclohexanothiazolyl, dihydroanthracene , tetrahydrocarbazolylpyridyl and the like. Preferably, it is a tetrahydrofuranyl group in R1. "Substitutable lower alkyl" or "substitutable alkyl" means lower alkyl or alkyl substituted by one to three substituents selected from the group consisting of 161077.doc -59· 201245190: Halogen atom 'lower cycloalkyl, phenyl (the phenyl group may be selected from a halogen atom 'CF3' lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a hydroxyl group and a dentate atom, a carboxyl group or a lower alkane One to three substituents in the alkyl group substituted by any one of the oxycarbonyl groups), a phenoxy group, a lower alkoxy group (the lower alkoxy group may be substituted by a lower alkoxycarbonyl group), a trifluoroantimony group Base, lower alkylthio, hydroxy, nitro, cyano, carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, lower alkyl alkoxy, amininyl, mono or disubstituted lower alkylaminocarbonyl, ring Aminocarbonyl, amine, mono or disubstituted lower alkylamino, cyclic amine, lower alkylsulfonylamino, benzenesulfonylamino, lower alkylamino, benzhydryl Amine, lower alkoxycarbonylamino, amidinoamine, mono or disubstituted lower alkylaminocarbonylamino, cyclic An aminomethylamino group, an amine sulfonyl group, a mono or disubstituted lower alkylaminosulfonyl group, a cyclic aminosulfonyl group, and a saturated or unsaturated heterocyclic group (the heterocyclic group may be selected from a dentate atom, a carboxyl group, a lower alkoxycarbonyl group, and one to three substituents in an alkyl group which may be substituted by any one of a halogen atom, a carboxyl group or a lower alkoxycarbonyl group; for example, a fluorenyl group, Ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, tert-butyl, methoxymethyl, methoxymethyl, 2-methoxyethyl, 2-decyloxy Propyl, cyclopropylmethyl, benzyldiphenylfluorenyl, benzyl, phenethyl, 3-phenylpropyl, 4-phenylene, hydroxymethyl, decyloxycarbonyl fluorenyl, hydroxy Carbonyl fluorenyl, amine methyl decylmethyl, 2-oxyethyl, 2-bromoethyl, 2,2-dichloroethyl, 2,2,2-trifluoroethyl, 2-aminoethyl, 3-apropyl, 3-nitropropyl, 3-cyanopropyl, 3-(methylamino)propyl, 3-(dimethylamino)propyl, 3-(bpy 161077.doc • 60- 201245190 pyridyl)propyl, cyclohexyldecyl, phenylfluorenyl, phenylethyl, 2% 4-nonylphenyl fluorenyl, 2, 3, or 4 methoxyphenyl fluorenyl, 2, 3, or 4- phenylmethyl, 2-, 3- or 4-fluorophenyl fluorenyl , % aminophenylmethyl, 3·dimethylaminosuccinylmethyl, 3·ethylaminophenylmethyl, % thiophenylmethyl, 2-, 3· or 4” ratio A dimethyl group (the K ring of the 2, 3, or 4 吼 基 methyl group may be selected from the group consisting of a primogen +, a m group, a lower oxy group, and a dentate atom, a carboxyl group, or a lower alkoxy group. Substituting one to three substituents in the alkyl group substituted by any one of the carbonyl groups, 5-benzoxazolylhydrazino group, 2-thienylfluorenyl group, 2-furylmethyl group, 2_ or 3_tetrahydrofuranylmethyl, 4-tetrahydroindole, butylmethyl, etc. When R3 is a "substitutable alkyl group", the substituent in R3 may, for example, be a phenyl group, a phenoxy group or a phenyl lower alkoxy group. a heteroaryl group, a heteroaryloxy group or a heteroaryl lower alkoxy group (the "heteroaryl group" is, for example, 5 to 1 member, preferably 5 or more, more preferably β to bite or „ a mercapto group or the like, further preferably an acridinyl group; etc.; as long as it is chemically tolerable, the substituents in the R3 may also be independently Any position of the aromatic ring (ie, phenyl or heteroaryl) is selected from the group consisting of a halogen atom, a CF3, a CN, a hydrazine, a carboxyl group, a lower alkoxycarbonyl group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, and a lower ring. 1 to 2 substituents in the alkyl group and lower alkoxyalkyl group; as long as it is chemically acceptable, the lower alkyl group, lower alkoxy group, lower alkenyl group lower cycloalkyl group and lower alkoxy alkane Further, the group may further be a carboxyl group, an aminocarbonyl group, a mono or disubstituted lower alkylaminocarbonyl group, a lower alkoxycarbonyl group, a Cl. 4 alkoxy group - a C2.4 alkoxy group or a via group at any position. C2-4 is substituted with an oxygen group or the like. The "lower alkenyl group which may be substituted" or "alkenyl group which may be substituted" means a lower alkenyl group or alkenyl group which may be substituted with one to three substituents selected from the group consisting of: 16I077.doc • 61 - 201245190 Halogen atom, lower cycloalkyl, phenyl 'phenoxy, lower alkoxy, trifluoromethoxy, lower sulfur, thiol, sulfhydryl, cyano, thiol, lower alkoxycarbonyl, oxygen Carbocarbonyl, amine mercapto, mono or disubstituted lower alkylaminocarbonyl, cyclic aminocarbonyl, amine, mono or disubstituted lower alkylamino, cyclic amine, lower alkylsulfonylamine a phenylsulfonylamino group, a lower alkylalkylamine group, a benzhydrylamino group, a lower alkoxycarbonylamino group, an amine mercaptoamine group, a mono or disubstituted lower alkylaminocarbonylamino group, a cyclic aminocarbonylamino group, an aminesulfonyl group, a mono- or disubstituted lower alkylaminosulfonyl group, a cyclic aminosulfonyl group, and a saturated or unsaturated heterocyclic group; for example, a styryl group , 2- or 3-phenylpropenyl, 3-phenylallyl, 4-(fluoro)styryl, 4-(methyl)styryl, 4-(methoxy)styrene , 4·(trifluoromethyl)styryl, 3-(4-fluoro)phenylpropenyl, 3-(4-methyl)phenylpropenyl, 3-(4-decyloxy)phenylpropene A group, a 3-(4-trifluoromethyl)phenylpropenyl group, a 2-(carboxy)vinyl group, a 2-(decyloxycarbonyl)vinyl group, or the like. The "lower cycloalkyl group which may be substituted" means a lower cycloalkyl group which may be substituted with one to three substituents selected from the group consisting of a dentin atom, a lower alkyl group, a lower cycloalkyl group, a stupid group, and a benzene group. Oxy, lower alkoxy, trifluoromethyl, trifluoromethoxy 'lower alkylthio, hydroxy, hydroxy lower alkyl 'nitro, cyano, carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, amine Mercapto, mono or disubstituted lower alkylaminocarbonyl, cyclic aminocarbonyl, amine, mono or disubstituted lower alkylamino, cyclic amine, lower alkylsulfonylamino, benzenesulfonate Mercaptoamine, lower alkylalkylamine, benzoylamino, lower alkoxycarbonylamino, amine mercaptoamine, mono or disubstituted lower alkylaminocarbonylamino, cyclic amine Carbonylamino group, amine sulfonyl group, mono or disubstituted lower alkyl group 161077.doc • 62· 201245190 Aminosulfonyl group and cyclic aminosulfonyl group; for example, 3 3_dicyclopentylbutyl group, 2- or 3-mercaptocyclopentyl, 2- or 3-fluorocyclohexyl, 2-, 3- or 4-methylcyclohexyl, 2-, 3- or 4-fluorocyclohexyl, 2-, 3- or 4- Cyclohexyl, 4,4-Dimethylcyclohexyl, 4,4-difluorocyclohexyl, 2- or 3-methoxycyclohexyl. "Substitutable lower cyclic ring group" means lower cycloalkenyl group which may be substituted with one to three substituents selected from the group consisting of a dentin atom, a lower alkyl group, a lower cycloalkyl group, and a phenyl group. ,phenoxy, lower alkoxy, trifluoromethyl, tri-methoxy, lower sulfur, hydroxyl, hydroxy lower alkyl, nitro, nitrogen, rebel, lower aerobic, benzyloxy Alkyl, amine broth, mono- or di-substituted lower alkylaminocarbonyl, cyclic aminocarbonyl, amine, mono- or disubstituted lower-grade amine, cyclic amine, low-grade refractory Amine, benzoic amine, lower indolylamine, benzhydrylamine, lower alkoxyamino, amine, mercaptoamine, mono or disubstituted lower alkylaminocarbonyl a base, a cyclic amino group amino group, an amine aryl group, a mono or disubstituted lower alkylaminosulfonyl group, and a cyclic aminosulfonyl group; for example, 2-mercaptocyclohexene-2 , 3-methylcyclohexen-2-yl, 4-methylcyclohexen-2-yl, 4-mercaptocyclohexen-3-yl, 4,4-dimethylcyclohexene-2 - Base, etc. • "Substitutable lower alkynyl group" or "substitutable alkynyl group" means lower alkynyl or alkynyl group which may be substituted with one to three substituents selected from the group consisting of a halogen atom and a lower ring. Alkyl, phenyl, phenoxy, lower alkoxy, trifluoromethoxy, lower alkylthio, hydroxy, nitro, cyano, carboxy, lower alkoxycarbonyl, oxycarbonyl, amine carbyl , mono or disubstituted lower alkylaminocarbonyl, cyclic aminocarbonyl, amine, mono or disubstituted, low 161,077.doc • 63· 201245190 alkylamino, cyclic amine, lower alkyl sulfonyl Amino, phenylsulfonylamino, lower alkylalkylamine, benzhydrylamine, lower alkoxycarbonylamino, amine arylamino, mono or disubstituted lower alkylaminocarbonylamino , a cyclic aminocarbonylamino group, an aminesulfonyl group, a mono or disubstituted lower alkylaminosulfonyl group, a cyclic aminosulfonyl group, and a saturated or unsaturated heterocyclic group; for example, a phenyl group An ethynyl group, a phenylpropan-1-alkynyl group, a 4-(fluoro)phenylethynyl group, a 4-(methyl)phenylethynyl group or the like. The "lower alkyl alkane group which may be substituted" means a lower alkyl fluorenyl group which may be substituted with one to three substituents selected from the group consisting of a functional element atom, a lower cycloalkyl group, a phenyl 'phenoxy group, and a lower stage. Alkoxy, trifluoromethoxy, lower alkylthio, hydroxy, nitro, cyano, carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, aminecarbamyl, mono or disubstituted lower alkylaminocarbonyl , cyclic aminocarbonyl, amine, mono or disubstituted lower alkylamino, cyclic amine, lower alkylsulfonylamino, benzenesulfonylamino, lower alkylalkylamine, benzo Mercaptoamine, lower alkoxycarbonylamino, amine mercaptoamine, mono or disubstituted lower alkylaminocarbonylamino, cyclic aminocarbonylamino, amidoxime, mono or disubstituted An alkylaminosulfonyl group, a cyclic aminosulfonyl group, and a saturated or unsaturated heterocyclic group; for example, a trifluoroethyl fluorenyl group, a trichloroethylene group, a decyloxycarbonyl group, or an ethoxycarbonyl group; Methoxyethyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and the like. The "substitutable phenyl group" and the "substitutable phenyl group" represent a phenyl group which may be substituted with one to three substituents selected from the group consisting of a halogen atom 'alkyl group (the alkyl group may be Lower alkoxycarbonyl substituted), phenyl 'phenoxy, lower alkoxy (the alkoxy group can be taken from a lower alkoxy group or a lower alkoxycarbonyl group, 16l077.doc •64-201245190 generation), trifluoromethyl, Trifluorodecyloxy, lower alkylthio, hydroxy, hydroxy lower alkyl, nitro, cyano, carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, aminemethanyl, mono or disubstituted lower alkylamino Carbonyl group, cyclic aminocarbonyl group, amine group, mono or disubstituted lower alkylamino group, cyclic amino group, lower alkylsulfonylamino group, benzenesulfonylamino group, lower alkylalkylamino group, benzene Alkenylamino, lower alkoxycarbonylamino, amine mercaptoamine, mono or disubstituted lower alkylaminocarbonylamino, cyclic aminocarbonylamino, amine sulfonyl, mono or disubstituted Lower alkylaminosulfonyl and cyclic aminosulfonyl; for example, phenyl, 2-, 3- or 4-phenylphenyl, 2-, 3- or 4-bromo Stupid, 2-, 3- or 4-fluorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 3,4-diphenyl, 3,5-dichlorophenyl , 2,3-dibromophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5.difluorophenyl, 3_chloro_ 2_ fluorophenyl, 4-vapor-2-fluorophenyl, 3-chloro-4-phenylene, 2-, 3- or 4-methylphenyl, 2-chloro-4-mercaptophenyl, 2 _ gas_5_mercaptophenyl, 2-fluoro-5-mercaptophenyl, 3-ox-4-mercaptophenyl, 3-fluoro-4-ylnonylphenyl, 4-gas-2-methyl Phenylphenyl, 5-chloro-2-methylphenyl, 5-fluoro-2-methylphenyl, 4-fluoro-3-methylphenyl, 2-, 3- or 4-decyloxyphenyl , 5-chloro-2-methoxyphenyl, 3-ox-4-methoxyphenyl, 2-, 3- or 4-aminophenyl, 4-nonylaminophenyl, 2-, 3- or 4-trifluorodecylphenyl, 2-nitro-3-trifluoromethylphenyl, 2-fluoro-3-3 trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl 4-cyclo-2-trifluoromethylphenyl, 4-fluoro-2-trifluoromethylphenyl, 4-ox-3·trifluoromethylphenyl, 4-fluoro-3-trifluoromethyl Phenyl, 3-dimethylaminophenyl, 2-, 3- or 4-cyanophenyl, 2-, 3- or 4-nitrophenyl, 4-biphenyl, 2-, 3- or 4- -trifluoromethane Stupid, 4-ethylthiophenyl, 2-, 3- or 4-pyridylphenyl, 4-carbyl 161077.doc •65- 201245190 phenyl, 2-, 3- or 4-carboxybenzene , 4-methoxycarbonylphenyl, 2-(methylsulfonylamino)phenyl, 4-(phenylsulfonylamino)phenyl, 2-, 3- or 4-(ethenylamine) Phenyl, 4-(benzylideneamino)phenyl, 4-(ethoxycarbonylamino)phenyl, phenoxyphenyl, and the like. The "substitutable naphthyl group" means a naphthyl group which may be substituted with one to three substituents selected from the group consisting of a dentate atom, a lower alkyl group, a phenyl group, a phenoxy group, a lower alkoxy group, and the like. Fluorinyl, trifluoromethoxy, lower alkylthio, hydroxy, hydroxy lower alkyl, nitro, cyano, carboxy, lower alkoxycarbonyl, benzyloxycarbonyl, aminyl, mono or disubstituted Alkylaminocarbonyl, cyclic aminocarbonyl, amine, mono or disubstituted lower alkylamino, cyclic amine, lower alkylsulfonylamino 'benzenesulfonylamino, lower alkyl fluorenyl Amino, benzhydrylamino, lower alkoxycarbonylamino, amine mercaptoamine, mono or disubstituted lower alkylaminocarbonylamino, cyclic aminocarbonylamino, amidoxime, a mono- or di-substituted lower alkylaminosulfonyl group and a cyclic amine-based flavonoid; for example, naphthyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-naphthalene Base, 2-, 3-, 4-, 5-, 6-, 7- or 8-decylnaphthyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-methoxy Naphthyl, 6,7-dibromo-2-naphthyl, 3-ethenylamino-1-naphthyl and the like. The "saturated or unsaturated heterocyclic group which may be substituted" means a saturated or unsaturated heterocyclic group which may be substituted with one to three substituents selected from the group consisting of a halogen atom and an alkyl group (the alkyl group). Substituted by a lower alkoxycarbonyl group, a phenyl group, a phenoxy group, a lower alkoxy group (which may be substituted by a lower alkoxy group or a lower alkoxycarbonyl group), a trifluoromethyl group, a trifluoromethoxy group, Lower alkylthio, hydroxy, hydroxy lower alkyl, nitro, cyano, carboxy, lower alkoxycarbonyl, 161077.doc -66 - 201245190 benzyloxycarbonyl, amine carbaryl, mono or disubstituted lower alkylamine a carbonyl group, a cyclic aminocarbonyl group, an amine group, a mono- or disubstituted lower-grade amine group, a cyclic amine group, a lower alkylsulfonylamino group, a benzenesulfonylamino group, a lower alkylalkylamine group, Benzylamino, lower alkoxycarbonylamino, amine carbylamino, mono or disubstituted lower alkylaminocarbonylamino, cyclic aminocarbonylamino, sulfonyl, mono or di The lower alkylaminosulfonyl group and the cyclic aminosulfonyl group are substituted; for example, pyrrolyl group, furanyl group, Thienyl, furyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, pyridyl, pyrimidine, hydrazine. Bizozolyl, fluorenyl, iso, oxazolyl, isoindole, succinyl, sulphate, p-indenyl, fluorenyl, tri. Sit, β-indenyl, benzofuranyl, benzodiazolyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, Isoquinolyl, 2-chloro-3-thienyl, 3-mercapto-2-thienyl, 2-methyl-3-. Alkyl, 4-mercaptoamino-3-»pyridyl, 6-cyano-2-isoquinolyl, oxetanyl, azetidinyl, beta 嘻β-based, four Hydrogen thiol, dioxolane, ° bottom, base, ph ph, high Ρ well base, tetrahydro η than thiol, thiocyclohexyl, imiline, thio-terinyl, The cycloheximide group, the dihydrogen sold saliva and η than the bite group, the tetrahydrothiazole D and the pyridine group and the like. The "mono- or di-substituted lower alkylamino group" and the mono- or di-substituted lower leumino group are represented by a group substituted with one or two lower alkyl groups on the amine group, and examples thereof include decylamine. A group, a dimethylamino group, an ethylamine group, a diethylamino group, an isopropylamine group or the like. In the compound represented by the formula of the present invention, when the bonding position of each substituent is not specified (here, the substituent means, for example, γ, R4, R5, 161077.doc -67 - 201245190

Ra2a

Ra3d allows, Ra2b, Ra2c, Ra2d, Ra2f, Ra2g, Ra3a, Ra3b, 尺山, Ra4a, Ra4b, Ra4c, Ra4d, 尺... and Ra4h), as long as it is chemically achievable, it can be bonded at any position. Each substituent. In the various production steps of the compound of the present invention, when the structure of the starting material contains a functional group which may participate in the reaction, such as an amine group, etc., it can be protected by introducing the protecting group which is usually used. Further, in this case, the target compound can be obtained by suitably removing the protecting group. In the various manufacturing steps of the compound of the present invention, when protection or deprotection is required, it can be carried out according to a known method, for example, Pr〇tective Gr〇ups h Organic Synthesis (Theodora W. Greene, Peter GM Wuts, John Wiley &; Sons, lnc·Published, 1999), etc. As the "protecting group for the amine group", a substituent which can be easily removed by reduction, hydrolysis or the like, which is generally used in the field of organic synthesis, such as Protective Groups in Organic Synthesis (Theodora W.)

In addition to the protecting groups described in Greene, Peter G. M. Wuts, John Wiley & Sons, Inc., '1999,' also refers to substituents that can be removed in vivo by enzymatic or non-enzymatic means. Examples of the "protecting group for an amine group" include, for example, a decyloxy group, an ethoxycarbonyl group, a 2,2,2-trisethoxycarbonyl group, an isobutoxycarbonyl group, an allyloxycarbonyl group, and a Tributoxycarbonyl, benzyloxycarbonyl, ethyleneoxycarbonyl, 9-fluorenyloxycarbonyl, fluorenyl, ethyl fluorenyl, propyl fluorenyl, phenyl fluorenyl, difluoroacetinyl, p-toluene Exact, phenyl, decyl, benzyl, 4-benzyloxybenzyl, 2,4-dimethoxyoxybenzyl, diphenylphosphonium 161077.doc • 68 - 201245190, triphenyl Methyl, trimethylacetoxymethyl, ethoxylated fluorenyl, ethoxylated methoxycarbonyl, ethoxycarbonylethoxycarbonyl, propylamino and the like. For example, P2 in the intermediate of the compound of the present invention represented by the formula (Ib) described in the above [41] represents 丨~3 phenyl groups (the phenyl group may be substituted by 1 to 2 methoxy groups) or C!_4 alkoxy-substituted sulfhydryl group, (c=〇)〇IlPi, or (C=〇)RP2, dentyl substituted) or Cw-alkenyl

Rpl represents a C,·4 alkyl group (the group may be substituted by 1 to 3 halogen atoms, wherein, in the case where the group is a fluorenyl group, a hydrogen atom may be represented by 丨~3 halogen atoms, phenyl or 9_R. , Cί·4 alkyl (the group may be substituted by 1 to 3 halogen atoms, wherein, in the case where the group is a Cw alkyl group, it may be substituted by 1 to 3 halogen atoms or Cm alkoxy group) or Phenyl, specifically, p2 may, for example, be a methoxy group, an ethoxy group, a 2,2,2-chloroethoxycarbonyl group, an isobutoxycarbonyl group, an allyloxycarbonyl group, or a third group. Oxyloxy 1 oxy (tetra), ethylene oxy (tetra), 9 benzyl methoxy, methyl fluorenyl, ethyl fluorenyl, (tetra)yl, benzhydryl, triethylene acetyl, f, 4 - methoxyl group, 2 red methoxy diphenyl f group, diphenylmethyl, trimethyl ethoxymethyloxy, ethoxylated, methoxy, methoxy methoxy And an ethoxyethoxy ethoxy group; etc.; preferably, 2,2,2-trichloroethoxy, propyleneoxy (tetra), tert-butoxycarbonyl, benzyloxycarbonyl, formazan Base, ^ ethyl, trifluoroethyl, benzyl, triphenylmethyl, etc.;佳 ^ . # ^ w 夕 1 Lifting the second butoxycarbonyl group, T-oxygen group, trifluoroethyl, benzyl stupid, sputum, etc., preferably the third butoxy carbonyl 161077.doc • 69 201245190 Group or Benzyloxycarbonyl group. Hereinafter, a method for producing the compound of the present invention will be described. The compound of the present invention represented by the formula (la) can be produced, for example, by the following production methods a to ^. The following mainly relates to the compound represented by the formula (Ia), which is carried out by the formula (Ia), but the compound other than the formula (Ia) in the compound represented by the formula (I) can also be obtained from the corresponding position by the following production method. The raw materials of the isomers were produced in the same manner.

Production Method A The compound represented by the formula [A] (hereinafter, also referred to as "compound A") in which the compound represented by the formula (la) is 'X is · N(R6)_, and γ is _c〇 can be used by For example, it is manufactured by the manufacturing method mentioned below. [化57]

(wherein R1 to R6 are as defined in the above [1], r is a lower alkyl group, and pl and P2 represent a protecting group of an amine group) [A-1 step] This step is carried out by a suitable solvent. 'Step of reacting compound a 1 with ammonia 161077.doc .70- 201245190 to obtain compound a2. The solvent used in this step can be selected from solvents and the like exemplified below, and is preferably methanol or water. More specifically, this step can be carried out, for example, by the method described in the step (1) of Reference Example 1 to be described later or the method according to the method. [Α-2 Step] This step is a step of obtaining a compound a3 by reacting the compound & 2 obtained in the above step with a compound. This step can be

Heter〇cycles, 55 (2001) 115-126 or the method described in the step (1) of Reference Example i described later, or the method according to the above. [Step A-3] This step is a step of obtaining a compound a4 by reacting the compound a3 obtained in the above A-2 step with methyl iodide in the presence of various bases in a suitable solvent. The base used in this step can be selected from the bases exemplified below, preferably '1'; 8_diazabicyclo[5 4 G]_7_decaine (10). The solvent used in this step can be selected from the solvents and the like exemplified below, and is preferably N,N. dimethylformamide (DMF). More specifically, this step can be carried out, for example, by the method described in the step (iii) of the reference example described later or the method according to the method. [Step A-4] This step is a step of obtaining a compound (IV) by allowing various oxidizing agents to act on the compound (IV) obtained in the above step A-3 by appropriate spraying. The oxidizing agent used in this step is, for example, m-chloroperbenzoic acid, nitrogen peroxide or the like, preferably m-chloroperbenzoic acid. The solvent used in this step can be selected from the solvents and the like exemplified below, and is preferably methylene chloride. More specifically, the method of the present invention can be carried out, for example, by the method described in the step (iv) of Reference Example 1 described later or the method according to the method. [Step A-5] This step is a step of obtaining a compound a6 by reacting the compound a5 obtained in the above A_4 step with the compound all in a suitable solvent in the presence of various bases. The base used in this step can be selected from the examples exemplified below and the like, preferably diisopropylethylamine and/or 4-didecylaminopyridine (DMAP). The solvent used in this step can be selected from the solvents and the like exemplified below, and is preferably a dioxin. More specifically, this step can be carried out, for example, by the method described in the step (v) of Reference Example 1 described later or the method according to the method. [Step A-6] This step is a step of obtaining a compound & 7 by deprotecting the protecting group p of the amine of the compound & 6 obtained in the above A_5 step. This step can be based on Protective Groups in 〇rganic Synthesis(The〇d〇ra w

Greene, Peter G. M. Wuts is carried out by 'J〇hn WUey & s〇ns, vol. 1999, or the method described in the procedure (Vi) of Reference Example 1 described later. [Step A-7]. This step is a step of obtaining a compound a8 by reacting the compound Θ obtained in the above step 66 with the compound al2 in the presence of a (iv) condensing agent in a suitable solvent. The condensing agent used in this step may be selected from the various condensing agents exemplified in the following step, and is preferably ethyl-3-(3-dimethylaminopropyl)carbodiimide (including a salt). Acid salt). In this step, the solvent used in 161077.doc •72- 201245190 can be selected from the solvents and the like exemplified below. More specifically, δ 'this step can be carried out, for example, by the method described in the first embodiment or the method obtained therefrom. [Α-8 Step] This step is a step of obtaining a compound & 9 by deprotecting the compound obtained in the above step -7, with the protecting group 胺 2 of the amine group. This step can be based on Protective Groups in Organic Synthesis (Theodora W.

Greene, Peter G. M. Wuts, John Wiley & s〇ns, - published, 1999), the method described in Example 2 or Reference Example 3 described later, and the like. [A-9 Step] This step is a step of obtaining a compound a from the compound a9 obtained in the above A-8 step by any one of the following reactions, (i) a substitution reaction: the substitution reaction uses an organic dentate compound (ie, R -Hal, wherein Hal represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom; or an organic sulfate compound (i.e., r3-os〇2Rl; where rl represents a Cw which may be substituted by a fluorine atom) The alkyl group or a phenyl group which may be substituted with a C?.4 alkyl group may, for example, be a methyl group, a trifluoromethyl group, a methylphenyl group or a phenyl group) (see, for example, "R3_L"; a leaving group, meaning a halogen atom or the above oso2rl); or (ii) a reductive amination reaction: I61077.doc -73- 201245190 The reductive amination reaction uses a compound having a mercapto group or a ketone group (ie, R3 is represented by R3'_C(R3, ')H- in R3 as defined in the above [1], and the compound having a mercapto group or a keto group is Rr-C(==〇)-R3"; Here, 'R3 represents a hydrogen atom, a lower alkyl group or a substituted phenyl group, and R3' is a portion of the "_C(R3'')H_" removed from R3 defined in the above [1]. The latter part) and a reducing agent such as NaBH(OAc)3 or NaBH3CN. The substitution reaction of the above (i) may be carried out in the presence of various bases in a suitable solvent, and the base and solvent may be selected from those exemplified below. More specifically, for example, it can be carried out by the method described in the third embodiment to be described later or the method according to the method. The substitution reaction of (1) can be used in the production method of the compound represented by the formula (Id) of the item [42]. In the reductive amination reaction of the above (ii), R3' in the compound having a mercapto group or a ketone group, that is, R3'-C(=〇)-R3'', more specifically represents a hydrogen atom, which may be substituted Lower alkyl, substitutable lower alkenyl, substituted lower cycloalkyl, substituted phenyl, substituted phenoxy lower alkyl, substituted phenyl lower alkoxy a lower alkyl group, a substituted heteroaryl group, a substituted heteroaryloxy lower alkyl group, or a substituted heteroaryl lower alkoxy lower alkyl group (the "heteroaryl group" is preferably 5 Preferably, the number of members is preferably 5 or 6 members, and further preferably pyridyl group or the like. As long as it is chemically achievable, the groups of R3 may be independently selected from any position. One or more substituents of a group consisting of a prime atom, CL, CN, 〇H&R3i; R3丨 is a hydrogen atom, a Ci4 alkyl group, a Cw alkane or a k alkoxy group _Cl.6 alkyl group 'the hydrogen atom , Ci6 alkyl, alkoxy and Ci.6 alkoxy_Cl 6 alkyl may be further substituted by gC〇2R32, 〇c〇R33 or 161077.doc • 74. 201245190 C(=0)NR34R35; R32, R3 3. R34 and R35 are each independently a hydrogen atom or a lower alkyl group. As long as it is chemically tolerable, the lower alkyl group may be further substituted at any position with more than one lower alkoxy group or hydrazine H, R3 Preferable examples thereof include a phenyl group, a phenoxy lower alkyl group, a phenyl lower alkoxy lower alkyl group, and a heteroaryl group (the "heteroaryl group" is preferably D or a decyl group or a ratio. Preferably, it is pyridyl) or the like; as long as it is chemically tolerable, each group of R3' may also be independently selected from a halogen atom, CF3, at any position of the aromatic ring (ie, phenyl or heteroaryl). 1 to 2 substituents in CN, OH, carboxyl, lower alkoxycarbonyl, lower alkyl, lower alkoxy, lower alkenyl, lower cycloalkyl and lower alkoxy lower alkyl; as long as it is chemically Allowing 'the lower alkyl, lower alkoxy, lower dilute, lower ring, and lower alkoxy lower alkyl can also be cyclized, amine carbonyl, mono or disubstituted at any position Alkylaminocarbonyl, lower alkoxy, C.4 alkoxy-C2-4 alkoxycarbonyl or Substituted with a -c2_4 alkoxycarbonyl group, etc. R3 represents a hydrogen atom, a lower alkyl group or a substitutable group as described above, preferably a hydrogen atom or a lower alkyl group. As the above compound R3'-C(=0)- In the case of R3", the compound r3Pi_c(=〇)_r3P2 represented by the formula (VIb) of the item [43] can be cited. That is, the reductive amination reaction can be used for the item [43] represented by the formula (Ie). In the method for producing a compound, in the formula (VIb), RW represents a group represented by any one of the formulas (43g), (4gp), (4hp) or (4ip), preferably represented by the formula (4gp) or 161077.doc • 75· 201245190 base shown by (4hp) is better represented by the formula (4hp). In the formula (4 rush), m... represents an integer of 〇~4 (wherein, in the case of one is !, m4hP represents an integer of Bu 4), preferably an integer representing 〇~2 (its ^, at this time n4h) , 广和广, respectively, independently represent an integer of 〇~3, and an integer of ιηΆρΊΗ; in the case of a ^^, an integer of 1 or 2), more preferably an integer of 〇 or 1 (wherein 1> When 411 is 1, ιη41Ί 1) ; Arm, Ra4h, Rb4h, Rd4h, Re4h, Rg' Rh4h, Ri4h, Rj4h, Rk4h,,,,,,,,,,,,,,,, as in the above [4] The definition is preferably as shown in the definition of any one of items [8] to [12]. In the formula (4gp), an integer representing 〇~5 is preferably an integer representing 〇~2, and Arm, RW, R and scale are as defined in the above item [4], preferably as The definition in [7] is shown. R3p2 is a hydrogen atom or a C.6 alkyl group as described in the item [43], and is preferably a hydrogen atom. The reductive amination reaction of the above (ii) can be carried out in a suitable solvent using various side-reducing agents or formic acid, and the solvent can be selected from those exemplified below. More specifically, for example, the following Example 19 can be used. Alternatively, the method described in the step (r7_i) of the seventh embodiment or the method according to the method can be carried out. The reductive amination reaction comprises the following two steps: (a) optionally in the presence of various acids or test media, or by dehydration using a Dean_Stark apparatus or a dehydrating agent, or in combination And the imide or imiline is formed from the amine compound and the amine compound, and (b) is reduced by the boron-based reducing agent or formic acid; it can be carried out in the same system (4) and 161077.doc • 76 - 201245190 (8), after carrying out (4), if necessary, perform separation, purification, solvent replacement, etc. as (4), reducing agent, for example, in addition to the above-mentioned atmosphere, sodium hydride, triethyl sulfonate side sodium hydride In addition, M乍 such as sodium chloride or 2-methylpyridine borane may be an acid catalyst, and an organic acid such as acetic acid or a Lewis acid such as tetrachloride (IV) may be used as a test medium. The choices exemplified in the following description are selected. Examples of the dehydrating agent include molecular sieves, anhydrous sodium sulfate, anhydrous magnesium sulfate, and the like. The compound represented by the formula (lb) of the item [41] can be synthesized in the same manner as the respective compounds of b3, e3 or d3 described later, in addition to the above. Each symbol defined in the item (4)], ^, [order (4), and each of the items (4) (for example, R1, R2, R3, r4, r5, χ, Ann, Ra4g, Ra4h,

Rb4h, Rb4i, Rd4g, Re4g, Rd4h i4h ni4h -, d4i ^t4i

R e4h

R f4h

Ri4h, Rj4h, Rk4h, R〇iM, Re4i, heart

R h4h RMi, m4h, n4h, p4h ς , η , Γ , S h , s41 , etc.) are preferably any one of the above items [7] to [20] '[36] to [38] or [39]. The definition in the middle. Further, the compound towel of the present invention produced by, for example, the reaction of the above (1) or (1)), etc., Rd4g, Rdg, Rd4h, Re4h, Rf4h, Rg4h, Rh4h, Ri4h'Rj4h'Rk4h'Rd4i^e4i>R^R- #^^[3].[4]. The definitions in [7], [9], etc., preferably independently of each other, and having a plurality of groups independently represent a hydrogen atom or a Gw alkyl group, respectively. More preferably, it represents a hydrogen atom. Or Rf4h and Rgu, as described in the item [9], may form a 3 to 6 membered cycloalkyl ring together with the bonded carbon atoms, and the cycloalkyl ring is preferably 3 to 5 members. More preferably, it is 3 members (i.e., a cyclopropane ring), and, as described in the item [3] or [4], independently represents 〇 or i, preferably 161077.doc -77· 201245190 0 'or in the case of one! In the case of 0, the other means 〇. Especially when Arm is a heteroaromatic ring (for example, pyridine ring or pyrazole is strict, r4h and s4h are preferably, ... denote 〇 , a case of _.1 [A-9' step] [Chem. 58]

This step is different from the above method for the production method of the compound A. This step is a preferred embodiment. [This step is achieved by the above-mentioned A_6 step by using various condensing agents in the lower field. The step of obtaining a compound A by reacting with the compound 313. This step; the condensing agent used by the household can be selected from the various condensing agents exemplified in the following description as 1-ethyl-3-(3-dimethylamine very high and *3 propyl propyl) succinimide (including Salt® II. The solvent used in this step can be used from the solvent or the like exemplified below. More specifically, this step can be, for example, the same as in the above-described step 7-1, as described in Example 1 or Example 87. The method described above is carried out. In more detail, 'this step is not limited to the above-mentioned use of a condensing agent,' may also activate the compound al3 or a salt thereof, as needed. The condensation reaction is carried out by reacting with the compound 37 or a salt thereof. Examples of the compound 'for example, the method for converting the (d) to the acid/nic acid liver or the like, or the above-mentioned method using the condensing agent 161077.doc - 78· 201245190 Law, etc. In the case of using the acid image method, first, the compound al3 and, for example, chloroform, sulfoxide, phosphorus, etc., in an inert solvent, in the presence or absence of an additive, Oxidation of a gasification reagent such as helium or five gasified phosphorus to obtain acid halogenation Here, as the additive, N,N-didecylguanamine, N,N-diethylguanamine, etc. may be mentioned. Examples of the inert solvent include dioxane, di-ethane or a halogenated hydrocarbon solvent such as chloroform; an aromatic hydrocarbon solvent such as toluene or diphenylbenzene; an ester such as ethyl acetate; etc. After the completion of the reaction, the reaction solution is allowed to be present in the presence of a hydrocarbon solvent such as a stupid or a stupid. Concentration under reduced pressure, the resulting acid compound is reacted with the compound a7 or a salt thereof in an inert solvent in the presence of a base, as needed, whereby Compound A or a salt thereof can be obtained. Here, as a base and a solvent, For example, in the case of the mixed acid anhydride method, when the compound & 13 or its salt is reacted with an acid complex in the presence of a base to obtain a mixed acid anhydride, the compound a7 or The salt is reacted to form a compound a or a salt thereof. Examples of the acid-toothed compound include methoxy methoxyhydrochloride, ethoxymethyl hydrazine chloride, and isopropoxy oxonium chloride chloroisobutylation. P-nitrophenoxypurine or butyl fluorene, etc. Here, as a test The solvent may be exemplified, for example, as exemplified in the following description, or various compounds may be used, and the compound a3 or a salt thereof and the compound a? or a salt thereof may be reacted in an inert solvent in the presence of an assay as needed. Production of Compound A or a salt thereof. In addition, a phase transfer catalyst or other additives may be used as the case may be. Here, the 'condensation agent can be cited as a lecture on experimental chemistry 161077.doc -79· 201245190 (曰本化学会编'Maru The person described in the 22nd volume, etc., for example, a carboxylic acid ester such as diethyl cyanophosphate or diphenyl azide; the above 1-ethyl-3-(3-dimethylamino group) A carbodiimide such as propyl)carbodiimide hydrochloride (wsc · HC1) or dicyclohexylcarbodiimide (Dcc); 2, 2, - 2 . a combination of a disulfide such as a pyridyl disulfide and a phosphine such as triphenylphosphine; N,N'-bis(2-oxo-3-oxazolidinyl)phosphorus (B0PC:1) Phosphorus halides; azodicarboxylates such as diethyl azodicarboxylate and phosphines such as triphenylphosphine; 2-nitro-1 -methylpyridine rust moths, etc. 2_halogen_ 1 _ Lower alkyl pyridinium halides; 1, fluorene-carbonyldiimidazole (CDI), azide diphenyl vinegar (DPPA), cyanophosphoric acid diethyl acetonate (DEPC), 2_(1Η_benzotriazolyl) )_1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), 2-(1Η-benzotrisyl)-1,1,3,3-tetramethyluronium hexafluorophosphate Ester (HBTU), benzobisoxalyl-1-yloxybis(dimethylamino) squamous (Β〇ρ), hexafluorodisic acid benzotriazol-1-yloxytri(pyrrole) Acridine-based (ΡΥΒΟΡ), 2·(7-aza·1Η_benzobisazol-1-yl)-1,1,3,3-tetramethylglycinate (hatU), or 2-gas _ 1,3-dimethylimidazole rust tetrafluoroborate (CIB) and the like. Examples of the inert solvent and the base include those exemplified below. Examples of the phase transfer catalyst include a tetrabasic salt such as tetrabutyl/smelred ammonium or benzyltriethylamine, or a crown ether such as 18-crown-6-ether, etc., and the case where the base is an inorganic base. . Examples of the other additives include 1-hydroxybenzotriazole (H0Bt), hydrazine-hydroxy-7-azabenzotriazole (HOAt), and the like, and the condensing agent is hydrazine·ethyl_3_(3 fluorenyl). A case of a carbodiimide such as an aminopropyl)carbodiimide hydrochloride (WSC · Ηα). Furthermore, the condensation reaction of the step -9-9 (that is, the above-mentioned method using the acid worm 161077.doc • 80 · 201245190) can be used for the method of the formula [45], the mixed acid liver method, and the condensing agent. The method of producing the compound represented by the formula (If). [A-10 Steps] [Chem. 59] A A-10 Q—cooh Q—COORa —_

A A1 This step is a step of converting the compound VIII obtained in the above step (where RRR, R, ruler or ruler 6 contains a vine group) into a corresponding acid reading compound (ι (the above reaction) Wherein q represents a moiety other than the ester group in the compound A, and RA represents a chemical group in the radical group. This step can be carried out according to the method described in Protective Groups in 〇rganic Synthesis (The〇d〇ra W. Greene, Peter G. M. Wuts^, John Wiley & Sons, Inc. '1999). More specifically, this step can be carried out, for example, by the method described in the second embodiment of the following or the method according to the method.

In the compound represented by the formula (la), the compound represented by the formula [B] wherein χ is _s_, Y* _c〇 (hereinafter, also referred to as "compound B") can be produced, for example, by the following Manufactured by the method. [60]

161077.doc 201245190 (wherein H1 to R5 are as defined in the above (1), Hal is a halogen atom 'P and P2 represents a protecting group of an amine group) [B-1 step] This step is by utilizing the above Step A-3 is the same as the method of reacting the compound a3 obtained in the above step A_2 with the compound to obtain the compound bl. [B-2 step; | This step is carried out by the same method as the above A_6 step. The step of obtaining the compound b2 by treating the compound bl obtained in the above-mentioned By step. [B-3 Step] This step is a compound b2it obtained in the above step by the same method as the above A-7 step. Step IB-4 step of obtaining the compound ^ This step is carried out by treating the compound obtained in the above step by the same method as the above-mentioned eighth step to obtain the compound (4). Step] 5 This step is a step of obtaining a compound represented by the formula [Β] by the method of the above-mentioned Α-9 step (and, if necessary, the Α_10 step, the compound obtained in the above step 44 step is obtained. .

Production Method C In the compound represented by the formula (la), χ is _c(r7)(r8), and γ is _c〇161077.doc •82· 201245190 The compound represented by the formula [c] (hereinafter, also referred to as "Compound c") can be produced, for example, by the following production method. [化61]

(In the formula, R1 to R5, R7 and R8 are a halogen atom as shown in the above (1), and p1 and P2 represent a protecting group of an amine group) [C-1 Step] This step is carried out by making the above A- The step of reacting the compound 35 obtained in the step 4 with the compound c5 to obtain the compound "more specifically, this step can be carried out, for example, by the method described in the step (χν) of the above-mentioned Example 18, or according to the method. This is carried out by the method [C-2 Step] This step is a step of obtaining the compound 〇2 by the same procedure as the above step Α6, to obtain the compound 一2. [C - 3 Step] This step is a step of obtaining the compound C3 by the treatment of the compound c2 obtained in the above c_2 step by the same method as the above step A-7. [c_4 step] 161077.doc -83 - 201245190 : : Step by using the same method as the above A_8 step, the compound obtained in the above C_3 is processed, and the step (4) is obtained. [C-5 step] This step is performed by using the above-mentioned part A. Step (and as needed A_i〇 step) the same method 'on the top The compound obtained in the CM step is subjected to a treatment to obtain a compound represented by the formula [C]. Further, for example, it can be produced by using the above-described production method c or a production method j described later, or a method according to the above. (4) In the compound of the present invention represented by YANG, the RW is as defined in the item (1) or the item [4], and preferably R7 and R8 each independently represent a hydrogen atom or a Ci 4 alkyl group is more preferably R. And at least any one of R8 is hydrogenogen +, and the other represents a hydrogen atom or a k-alkyl group.

In the compound represented by the formula (la), the compound represented by the formula [d] wherein X is 〇 , and γ is _c 〇 _ (hereinafter, also referred to as "compound Dj" can be, for example, the following Manufactured by the manufacturing method. [Chem. 62]

(wherein R to R5 are as defined in the above [1], pl & p2 represents an amine group 161077.doc • 84· 201245190 protecting group) [D-1 step] This step is due to various bases In the presence of a suitable solvent, the compound a5 obtained in the above step A4 is reacted with the compound d5 to obtain a mouth dl. The base used in this step can be selected from the bases and the like exemplified below, and is preferably sodium hydride. Step P-2] This step is carried out by treating the compound dlit obtained in the above-mentioned step in the same manner as in the above-mentioned step A-6 to obtain a compound (four). [D_3 step] This step is to treat the compound d2it obtained in the above d_2 step by the same method as in the step A-7 of Ao Shangcheng A 7 Doug · ri, and obtain the step of compound (4) [D- 4 Step] In the same manner, the step of obtaining the compound d4 for the above D_3 is carried out by treating the compounds obtained in the step of the above A_8 step. [D-5 step] This step is performed by Compound D4 obtained by T listening in the above D_4 step is treated in the same manner as in the above-mentioned A-9 step, and as in the case of A_1〇, to obtain a compound represented by formula P]. And the method of the present invention can be produced, for example, by using the above-mentioned production method D, a production method or a production method J described later, or a method according to the above, etc., in the compound of the present invention. 'R2 is not defined in items (1), [3], (4), [17] ~ [2〇], etc., preferably R2 is as defined in the item [2〇], and more preferably In the formula (3a), 'Ra3a' represents the substitution of the Ci_6 alkoxy group at the position (position 3) with the alkoxy group.

In the compound represented by the formula (la), the compound represented by the formula [E] (hereinafter, also referred to as "compound E") of ^^_c(〇)nr9k(〇)〇 can be, for example, the following Manufactured by the manufacturing method. [化63]

(wherein R^R5 and X are as defined in the above [1], ζι is NR9 or 〇 (where 'R9 is as defined in the above [1]), and p2 represents the protection of an amine group. (E-1 step) This step is to add a phosgene to the compound a7, b2, c2 or d2 obtained by the production methods A to D in the presence of various tests, and then add the compound e4. This is the step of obtaining compound e2. More specifically, this step can be carried out, for example, by the method described in the above-described Example 84 or the method of 161077.doc-86-201245190. [E'2 step] The step of obtaining the compound ^ by the treatment of the compound 62 obtained in the above step E-1 by the same method as the above-mentioned step A_8 [E-3 step] This step is The compound obtained in the above step E-2 is subjected to the same procedure as in the above step A-9 (and the step A-1 as needed). The step of carrying out the treatment to obtain the compound represented by the formula [E]. More specifically, the above E-2 step and this step can be carried out, for example, by the method described in the above-described Example 85 or the method according to the method. Production Method Ea In the compound represented by the formula (la), the compound represented by the formula [Ea] wherein Y is _c(S)NR9- or -C(S)〇- (hereinafter also referred to as "compound Ea") It can be produced by, for example, the following production method. [化 64]

E3a Ea (wherein R1 to R5 and X are as defined above), Z1 is NR9 or 161077.doc • 87- 201245190 〇 (here, R9 is as defined in [1] above) ), p2 represents a protecting group of an amine group) /Λ [Ea-1 step] This step is a compound a7, b2, α or d2 obtained by the production methods A to D, except in the presence of various bases, if necessary Further, in place of the triphosgene, a step of obtaining the compound e2a by the same method as the above [E_step] is used except that phosgene or 1,1 thiocarbonyldiimidazole is used. [Ea-2 step]~[Ea-3 step] These steps are carried out by treating the compound e2a obtained in the above Ea-Ι step by the same method as the above steps E-2 and E-3, The step of obtaining a compound represented by the formula [Ea] is obtained. Further, in the compound represented by the formula (1) in the compound E and the compound Ea, the compound represented by the formula (II) and the formula (V). In the formula [工], R9 represents a hydrogen atom, a lower alkyl group which may be substituted, a lower cyclohexyl group which may be substituted, a phenyl group which may be substituted or a saturated or unsaturated group which may be substituted The heterocyclic group preferably represents a hydrogen atom or a lower-substituted alkyl group which may be substituted, and more preferably represents a hydrogen atom. In the formula (11) and the formula (V) of the item [1], z represents an oxygen atom or a sulfur atom, and preferably represents an oxygen atom.

Production Method F In the compound represented by the formula (la), the compound represented by the formula [F] wherein 丫 is _s〇2 (hereinafter, also referred to as "compound F") can be produced by, for example, the following production method. Manufacturing. [Chem. 65] 161077.doc •88- 201245190 ΗΝ Ο

R1 , R2 Ν,, Χ (= a7, b2, c2, d2) F-1 F-2 P2 A R4 rl'7^SxC> P2' f2 f4

R4°V? U , HNd〇0C F-3

N', X R3_ f3 (wherein X and R1 to R5 are as defined above), and P2 represents a protecting group of an amine group. [F-1 Step] This step is due to various tests. In a suitable solvent, the compound a7' b2 obtained by the above-mentioned production methods A, B, C & D, the core or "the reaction with the compound f4 to obtain the compound ? 2. The solvent used in this step may be used. It is selected from the solvents and the like exemplified below. More specifically, this step can be carried out, for example, by the method of § s in the step (ex2 〇 8 i) of the embodiment 208 described later, or the method according thereto. [F-2 Step] This step is a step of obtaining compound f 3 by deprotecting the protecting group P of the amine group of the compound f2 obtained in the above step F-1. This step can be carried out, for example, by the above. The method described in the step A-8 or the step (ex2〇8-ii) of the embodiment 208 described later, or according to the method obtained by the method. [F-3 step] This step is performed by using the above-mentioned A- 9 steps or the same steps as the steps (ex208-Ui) of Example 208 (and as needed in step A-10), in the above step f_2 F3 is obtained compounds of processing, a step of obtaining the formula [F] represented by the compounds. 161077.doc • 89- 201245190

Manufacturing Method G

Among the compounds represented by the formula (la), the compounds B, C and D obtained by the above production methods b, c and D can also be produced, for example, by the following production method. [化66]

(wherein, X represents an oxygen atom, a sulfur atom or _Cr7R8_, r]~r5, r7&r8 are as defined in the above [1]) [G-1 step] This step is performed by -9. The same procedure as in the step of obtaining the compound b, c or D by reacting the compound b2 or compound obtained by the above production methods B, C and D with the compound al3. Hereinafter, the method for producing an intermediate of the compound of the present invention will be described. Production Method 化合物 The compound a6, bl or dl which is an intermediate of the above-mentioned production method A, hydrazine or D can be produced, for example, by the following production method.

A6 (X = N-Re) b1 (X = S) d1 (X = 〇) a11 (X = N-Re) h3 (X = S) d5 (X = 0) (wherein X represents oxygen atom, sulfur Atom or _N(R6)_, Ri, R2&R6 are as defined in 161077.doc -90· 201245190 above, R is a lower alkyl group, and pi represents a protecting group of an amine group. [H-1 This step is a step of obtaining a compound hl by reacting the compound a2 obtained in the above Aj step with the compound h2 in the same manner as in the above step A-2. More specifically, this step can be carried out, for example, by the method described in the step (M-i) of Reference Example 4 to be described later or the method according to the method. [H-2 Step] This step is a step of obtaining a compound ", by reacting the compound obtained in the above step with the compound a", h3 or d5. This step can be carried out by the method described in The Journal 〇f (4) 72 (2007) 10194.1021 〇 or the step (4) i) of the reference example described later, or the method according to the above.

The production method I can be produced, for example, from the compound of the above-mentioned production method C, from the compound c of the oxime, for example, by the production method described above. [68]

T-5

I5 18 ho2c

161077.doc -91 ¢1 201245190 (wherein R and R" indicate lower alkyl or form a cyclic amine with N bonded to the group, R1, R2, 尺 7 and R8 in _ KR and 11 As defined in the above Π], p represents a protecting group of an amine group. [1-1 Step] This step is to react the hydrating agent 11 with an amine by the presence of a suitable solvent and an acid catalyst. The step of obtaining compound 12 is obtained. Is the acid catalyst used in this step preferably correct? Benzene. The amine oxime prepared in this step is a secondary amine, preferably a porphyrin. The solvent used in this step can be selected from the solvents and the like exemplified below, and is preferably abbreviated. [1-2 Step] ^ This step is a compound obtained in the above M step by a suitable solvent. The compound is obtained by reacting with isocyanate h2. A step of. This step can be carried out by the method of the literature or by the method obtained therefrom. [1-3 Step] This step is a step of obtaining the compound i4 as an aqueous acid solution, preferably hydrochloric acid, by treating the compound i3 obtained in the above step with an aqueous acid solution in a suitable solvent. The solvent used in this step is selected from the solvents and the like exemplified below, and is preferably toluene. More specifically, the above steps can be carried out, for example, by the method described in Reference Example 5 (the method described in the following, or the method according to the method). [1-4 Procedure] This step is performed. The compound 14 obtained in the above steps 1-3 is treated in the same manner as the above step A-1 to obtain the step 161077.doc-92·201245190 of the compound i5. More specifically, this step For example, it can be carried out by the method described in the steps (8) and π) of Reference Example 5 to be described later or the method according to the method. [1-5 Step] This step is a step of obtaining the compound i6 by treating the compound 丨5 obtained in the above 14 step with various tartare i8 and filling gas in the presence of (d). The base used in this step can be selected from the bases and the like exemplified below. Than <. More specifically, this step can be carried out, for example, by the method of Reference Example 5 described later (the method described in Γ5-Η〇, or the method according thereto). 1>6 Steps This step is performed by the upper illusion. In the case of the compound obtained in the step 5, the step can be carried out, for example, by the method of the second step (h), or the method of the reference step 5 (hereinafter referred to as (9), or This is done according to the methods obtained.

The compound dl which is an intermediate of the above production method D can be produced, for example, by the production method described above. [化69] Ο Ρι«

J-1 p, 'cCx: h1 Γι Amino group (wherein, and R2 is as defined in the above (1), ρ1 represents a protecting group) [J-1 step] 161077.doc -93- 201245190 This step is The compound obtained in the above step is reacted with an alkylating agent in the presence of a suitable solvent in the presence of various tests to obtain (4). The domesticating agent used in this step (that is, also referred to as RL), L is a leaving group, indicating a halogen atom or 〇s〇2rL described below) means an organic halogen compound (ie, R2_Hal; here, Hai represents a halogen atom) Preferably, a chlorine atom, a bromine atom or an iodine atom) or an organic sulfate compound (i.e., R -OS〇2RL; here, a c which can be substituted by a fluorine atom)*alkyl is formed by "C〗· The phenyl group substituted by the four-group base may, for example, be a mercapto group, a triterpene, a tetramethylphenyl group or a phenyl group. The test used in this step can be selected from the bases and the like exemplified below, and is preferably potassium carbonate. The solvent used in the present step can be selected from the solvents and the like exemplified below, and is preferably N,N-didecylguanamine. More specifically, the present step can be carried out, for example, by the method described in the step (r6-ii) of Reference Example 6 described later or the method according thereto. Production Method 化合物 The compound ai3 which is an intermediate of the above production method and G can be produced, for example, by the following production method. [化70]

161077.doc •94· 201245190 (wherein R is a lower alkyl or benzyl group, and R3, R4&R5 are as defined in the above (1)) [K-1 step] This step is carried out by using formazan The step of obtaining a compound a3 from the compound k1 by a reductive amination reaction of a compound of a ketone group or a ketone group with a reducing agent such as NaBH(OAc)3 or NaBHKN. The reductive amination reaction is the same as (ii) in the above step A-9. More specifically, this step can be carried out, for example, by the method described in the step (r7-i) of Reference Example 7 described later or the method according to the method. Wherein R is represented by r3'_c(r3,.)h_ in the rule 3 defined in the above [1], and the compound having a thiol or keto group is R3, _C(=〇)_R3· Here, R3 represents a hydrogen atom, a lower alkyl group or a substituted phenyl group, and R3' is a portion obtained by removing the "_C(R3")H_" portion from R3 defined in the above [1]. More specifically, R3' represents a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower cycloalkyl group which may be substituted, a substituted phenyl group, a fresh phenoxy group (4) 彳 County-like phenyl lower alkoxy lower alkyl, substituted heteroaryl, substituted heteroaryloxy lower-grade, or substituted heteroaryl lower alkoxy lower-grade (The "heteroaryl group" is preferably 5 to 10 members, more preferably 5 or 6 members, and further preferably a pyridyl group or a pyrazolyl group, etc.); as long as it is chemically acceptable, each of R3 may also be used. Each of R31 selected from the group consisting of a _ _ _ _ _ _ _ _ _ _ _ _ _ _ CU6 alkyl, (^.6 alkoxy, I61077.doc -95- 201245190 base 'the hydrogen atom, CN6 alkyl group, Cw alkoxy group and CN6 alkoxy-Cw alkyl group may further be passed through CO 2 R 32, OCOR 33 or C(=0)NR34R35 is substituted; R32, R33, R34 and R35 are each independently a hydrogen atom or a lower alkyl group, and as long as it is chemically acceptable, the lower alkyl group may be optionally Further substituted by more than one lower alkoxy group or OH. The ruthenium 3 _ preferably exemplified by a phenyl group, a phenoxy lower alkyl group, a phenyl lower alkoxy lower alkyl group, a heteroaryl group (the heteroaryl group) The group "preferably a pyridyl group or a pyrazolyl group or the like is more preferably a pyridyl group" or the like; as long as it is chemically acceptable, each group of R3' may also be independently an aromatic ring (i.e., a phenyl group or a heteroaryl group). Any position selected from the group consisting of a halogen atom, a CF3, a CN, an OH, a carboxyl group, a lower alkoxycarbonyl group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, a lower cycloalkyl group, and a lower alkoxy group. 1 to 2 substituents in the substitution; as long as it is chemically tolerable 'the lower alkyl, lower alkoxy, lower base, lower cycloalkyl and lower alkoxy lower alkyl may be further in any position a thiol group, an aminocarbonyl group, a mono or disubstituted lower alkylaminocarbonyl group, a lower calcination group, a Cl.4 alkoxy-C2-4 aerobic group or a group of alkoxysilanes Substituent substitution. R3'' is preferably a hydrogen atom or a lower alkyl group. [K-2 Step [K-4 Step] [K-2 Step Bu [K-4 Step] The next step is a step of protecting the compound k1 as a carboxylic acid body into a suitable lower alkyl ester body or a vinegar body, that is, compound k2, by using an organic halogen compound (ie, R3_Hai; here, Hal represents a halogen atom, Preferably, a gas atom, a bromine atom or a broken atom) or an organic sulfate compound (ie, 'r3-〇S〇2Rl; here, rl represents a benzene which can be substituted by 161077.doc -96-201245190 I.4 alkyl Base, can be listed

Compound k3 was deprotected to give compound al3. The C 1.4 substituent substituted by a gas atom may be C 1 methyl, trifluoromethyl, 4-methylphenyl, or 5 may be carried as "R-L"; L is a heterogeneous compound to obtain compound k3, and then. The substitution reaction in this step can be carried out in the presence of various bases in a suitable solvent. The base and the solvent can be selected from those exemplified below, and more specifically, for example, it can be carried out by the following Example 3. The method, or the method according to it, is carried out. The protection and deprotection of the carboxylic acid can be carried out in accordance with the method described in the above Protective Gr〇ups in 〇rganic Synthesis. Further, the compound & 13 which can be produced by the present production method K contains the compound represented by the formula (VII) of the item [44], and the case where the rule 3 of the compound a 3 is the formula (4h) in the item [4] In the meantime, the compound al3 is a compound represented by the formula (νπ). That is, the present production method can be used in a method for producing a compound represented by the formula (VH). In the formula (VII) of the item [44], 'Rb4h' is as defined in [44], preferably C02R3g4 (wherein R3s4 represents a cN4 alkyl group). Further, similarly, in the formula (VII), Arm, Ra4h, Rd4h, Re4h, Rf4h, Rg4h, Rh4h, Ri4h, Rj4h, Rk4h, m4h, n4h, p4h, q4h, r4h, s4h, 仗4 and 尺5 As shown in the definition in the above [4], it is preferably as defined in [8], [12] or [39]. Production method Ka A compound represented by the formula [al3a] (hereinafter also referred to as "compound al3a") contained in the compound al3 which is an intermediate of the above-mentioned production methods A and G. 161077.doc • 97- 201245190 Manufactured by the following manufacturing method. [化71]

Ka-1 R4 ί ?神 Ο

► d4h (wherein Rb4h is the ester defined in [44] above, Arm, Ra4h, rc

Rf4h, Rg4h, R4 and R5 are as defined in the above [4]) [Ka-1 step] This step is carried out by reacting the compound kla with the compound by the same method as the above K" step. The step of obtaining compound k2a. More specifically, this step can be carried out, for example, by the method described in the step of Reference Example 7 to be described later or the method according to the method. ° [Ka-2 step] The white t step is a reduction reaction of the compound obtained in the step ΐ1^·1, which is reduced to an early bond, for example, in various metal catalysts (such as; The step of obtaining a compound is carried out in the presence of a hydrogenation reaction or a reduction reaction using a hydride reducing agent. Further, the method is the same as the method described in Reference Example 7 (the method described or the method according to the method described below). The compound a3a produced by the manufacturing method (4) includes the above [4]. The compound represented by the formula (VII) is produced by the method of the production method of the compound 〇 Α 化合物 。 。 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 161 72] H2N ml /R1 M-1 SCN a1〇R1 (wherein R1 is as defined in the above [1]) [M-1 step] This step is carried out by a suitable solvent to make the compound ml and The step of obtaining a compound aO by a sulfur phosgene reaction. The solvent used in the step can be selected from the solvents and the like exemplified below, and is preferably a two-layered gas of dioxane and water. More specifically, s ' This step can be carried out, for example, by the method described in the reference example of the following, or the method according to the method described in the above, and the use of the reagent R3-L described in the production method A, the production method κ, and the like. The substitution reaction of heterocyclic butane nitrogen is represented by using the Buchwald-Hartwig reaction. In the presence of a metal catalyst such as a medium or a copper catalyst, and a suitable test, the conditions of the usual various coupling reactions for combining an aromatic dentate compound or an aromatic sulfate compound with an amine can not only produce R3 but also The compound of the present invention may be, for example, a compound of the present invention in which R3 is a substitutable aryl group, a substituted heteroaryl group or the like. The compound as a raw material and an intermediate in each of the above production methods (here) The compound is, for example, the compounds al, al, all, al2, ai3, b5, C5, d5, e4, f4, h2, h3, il, i7, i8, kl, kla, ml, r2-L, RL and R3 -C(=〇)-R3") may be used as a commercially available compound, or may be produced by a commercially available compound by a known method. 161077.doc • 99- 201245190 The compounds used in the above various manufacturing methods may also be formed. The salt is the same as the above-mentioned salt of the compound of the present invention. The test used in each of the above-mentioned production methods is suitably selected according to the type of the reaction or the raw material compound, etc., for example, sodium hydrogencarbonate hydrogencarbonate. Potassium hydrogencarbonate , * anaesthetic acid, carbonic acid unloading and other acid-killing tests; hydrogen hydride, hydrogenated metal and other metal hydride; sodium hydroxide, potassium hydroxide and other alkali metal hydroxides; sodium citrate, sodium butoxide sodium and other alkali metals Alkanol salts; organic metal bases such as butyl lithium and diisopropyl amide amine; triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1,8- An organic test such as a diazabicyclo[5 4 〇] 7·11 thinner (DBU). The solvent used in each of the above production methods is appropriately selected depending on the type of the reaction or the raw material compound, for example, decyl alcohol, ethanol, Alcohols such as isopropanol; ketones such as acetone and fluorenone; todenated hydrocarbons such as methane and gas; tetrahydrofuran (THF), ethers such as dioxane; aromatic hydrocarbons such as toluene and benzene; Aliphatic hydrocarbons such as Gengyuan; vinegars such as ethyl acetate and propylene acetate; amides such as N,N-dimethylformamide (DMF) and N-methyl-2-pyrrolidone; An anthracene such as methyl sulfoxide (DMSO) or a nitrile such as acetonitrile; these solvents may be used alone or in combination of two or more. Further, depending on the type of reaction, an organic test may be used as a solvent. The reaction temperature in each of the above production methods is appropriately selected depending on the reaction or the starting material compound, the type of the solvent to be used, and the like, and is usually _i 〇〇 ec to 200 ° C, preferably _7 〇 ° C to 100. (: The reaction time in each of the above production methods should be appropriately selected depending on the reaction or the starting compound, or the kind of the solvent to be used, etc., and is usually (7) minutes to 161077.doc 100-201245190 48 hours' is preferably 30 minutes~ 24 hours. The intrauterine groups within 5 molecules of each compound including the intermediates obtained in the above respective production methods can be combined by a known method, for example,

The method described in Comprehensive Organic Transformations (Richard C. Larock, 'John Wiley & s〇ns, Inc., 1999) is converted into a target functional group. For example, a compound having a carboxylic acid alcohol or a primary or secondary amine in the present invention can be used as an intermediate, and can be converted into other vinegar, guanamine, amino citrate, etc. which are used as MGAT2 inhibitors. A compound of the invention. The product obtained in each of the above production methods can be isolated and purified according to a usual method such as extraction, column chromatography, recrystallization, and reprecipitation. A salt which is physiologically acceptable as a physiologically acceptable acid, an alkali metal salt, an alkaline earth metal salt or a salt with an organic base. Specific examples of the acid addition salt include, for example, mineral acid salts such as hydrochloride, hydrobromide, hydroformate, sulfate, and salt, and oxalate, maleate, and antimony. Dibasic acid salt, malonate, lactate, malic acid, citrate, tartrate, acid salt, methyl acid salt, p-toluene acid salt, gluconate, and the like. Examples of the alkali metal ruthenium include inorganic (iv) such as a sodium salt and a potassium salt; and, for example, a soil-measuring metal salt, for example, a salt of a salt or a magnesium salt; and a salt of the form of an organic base, for example, ammonia. a salt of f amine, triethylamine or N-methyl morpholine. As a preferred embodiment, the compound of the present invention can be formed into an acid addition salt. The acid which can be used is preferably hydrochloric acid, acid-filled acid, transbuteroic acid, etc. The so-called "chemically stable salt", It means an acid addition salt, a metal salt, an alkaline earth metal salt or a salt with an organic base having a storage stability to the extent permitted by 161077.doc 201245190 -y 曰 ° in a chemical reaction. Specific examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphoric acid, and acetate, trifluoroacetate, and oxalate. Cis-butyric acid, C t* . Muscle fumarate, malonate, lactate, malic acid: citrate, tartrate, benzoate, methanesulfonate, benzenesulfonic acid An organic acid salt such as a p-supply acid salt or a (tetra) sugar acid salt. For example, examples of the soil-measuring metal 4 include a calcium salt and a magnesium salt, and examples of the organic base include, for example, ammonia, methylamine, and the like. The salt of ethylamine and N-methyl syrup is not limited to these. The compound represented by the formula (I) and the physiologically acceptable salt thereof are also present in the form of water and/or a cold composition, and thus the hydrates and solvates are also included in the present invention. Within the compound. In addition, since the compound represented by the formula (I) has a π having more than one asymmetric carbon atom, the ub also has geometrical or axial chirality = brothers, and thus there may be various stereoscopic differences. Structure. These stereoisomers: , etc. The compounds and racemates are also included in the compounds of the present invention. Further, the present invention also encompasses all tautomerizations of the compounds of the present invention. Further, the present invention encompasses physiologically acceptable salts and/or solvates thereof. The compound represented by the formula (I) is pre-druged, or the present invention also includes the hydrates of the present specification. The term "precursor represented by the formula (I) is 161077.doc 201245190 broad," And a compound which is converted into a compound of the formula (1) by a reaction caused by an enzyme or a gastric acid or the like under a physiological condition in the body, for example, a compound which is converted into a compound of the formula (1) by enzymatic oxidation, reduction, hydrolysis or the like. A compound which is converted into a compound of the formula (1) by hydrolysis of gastric acid or the like. Specifically, for example, a compound of the present invention containing a (tetra) acid, an alcohol or a grade or a secondary amine can be converted into vinegar, guanamine, urethane, etc. which can be easily hydrolyzed by the above reaction in vivo. The resulting compound is preferably vinegar. In addition, the compound of the present invention also contains a pre-drug "price" (7) in the present specification, the term "pre-effect drug" refers to the use of enzymes, etc. under physiological conditions in vivo after performing the desired effect. A compound that causes a reaction (for example, enzymatic oxidation, reduction, hydrolysis, etc.) to be rapidly converted into a compound having a relatively low burden on a living body (unwanted side effects, etc.). Specifically, for example, a compound such as an ester, a guanamine or a urethane which can be easily hydrolyzed by a reaction caused by an enzyme in a living body or the like can be used, and an ester is preferable. Further, a ruthenium transformant obtained by converting one or two or more of the compounds of the present invention into H (D) is also included in the compound of the present invention. The ruthenium converters can be obtained by a known method: synthesis from a commercially available compound or reagent which has been previously deuterated, or hydrogenation using hydrazine, or use of a hydrazine reducing agent (for example, 'boron bismuth hydride, etc. The reduction reaction, etc. Further, depending on the reaction conditions, the compound of the present invention can be obtained in the form of a salt, a free acid or a free base which can be converted into a desired salt, a free acid or a free base by a usual method. The compound of the present invention or a physiologically acceptable salt thereof may also be a crystal, and the 161077.doc • 103-201245190 or the like can be obtained by a known crystallization method or the like. In the case where the compound of the present invention or a physiologically acceptable salt thereof can take a plurality of crystalline forms, all of the crystalline forms are included in the compound of the present invention. Where the compounds of the invention may exist as optical isomers, stereoisomers, rotary isomers and/or positional isomers, such are also included in the compounds of the invention. These can be obtained by a known method such as synthesis from an optically active raw material compound or a separation method such as an optical separation method or a preferential crystallization method. The compound of the present invention or a physiologically acceptable salt thereof has an MGAT inhibitory action and can be used as a prophylactic and/or therapeutic agent for MGAT-related diseases. The term "MGAT-related diseases" refers to a disease caused by excessive accumulation of neutral fat or abnormal metabolism of neutral menstrual fat in the body, such as obesity, metabolic syndrome, and high disease. Lipemia, hyper-slipemia, high VLDL (here, "VLD] L" means very l〇w-density lipoprotein), hyper-fatty acidemia, diabetes, arteriosclerosis Symptoms, etc. Therefore, the compound of the present invention and physiologically acceptable salts thereof can be used for the prevention of obesity, metabolic syndrome, hyperlipidemia, hyper-slipemia, hyperemia, sputum fatty acidemia, diabetes, atherosclerosis And/or a therapeutic agent. When the compound of the present invention or a physiologically acceptable salt thereof is used as a MGAT inhibitor, any of the administration methods of oral administration, parenteral administration or intrarectal administration may be employed, preferably oral administration. . The dosage is not according to the administration method, the patient's symptoms, age, treatment form (prevention or treatment), etc., and is usually 161077.doc •104· 201245190, usually 10 ng/kg/day~l〇mg/kg/day Preferably, it is ~1 mg/kg/day, and further preferably i is /]^/day~1〇〇gg/kg/day i day i or divided into 2 times to 3 times. In addition, it can be administered once every few weeks to several weeks. Alternatively, the adult is administered once per day or divided into 2 times to 3 times i pg/gq g/day, preferably 10 pg/day to 100 mg/day, and more preferably 1 〇〇pg/day~ 10 mg / day. In addition, it can be administered every few days to several weeks. The compound of the present invention is usually administered as a carrier for the preparation in the form of a preparation prepared by mixing with a carrier for preparation, and a substance which is commonly used in the field of preparation and which does not react with the compound of the present invention can be used. Specific examples thereof include lactose, glucose, mannitol, dextrin, starch, white sugar, magnesium metasilicate aluminate, synthetic aluminum citrate, crystalline cellulose, sodium carboxymethylcellulose, and hydroxypropyl starch. , carboxymethylcellulose calcium, ion exchange resin, methylcellulose gelatin, gum arabic, hydroxypropylcellulose, low degree of substitution propylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone , polyvinyl alcohol, light phthalic anhydride, magnesium stearate, talc, stilbene ethylene polymer 'titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin, purified lanolin, Glycerin gelatin, polysorbate, polyethylene glycol, vegetable oil, hydrazine, nonionic surfactant, propylene glycol, water, and the like. The dosage form may, for example, be a tablet, a capsule, a granule, a powder, a syrup, a suspension, a suppository or a gelling agent. These preparations can be prepared according to the usual methods. Further, when the liquid preparation is prepared, the form H which is dissolved or suspended in water or other suitable medium at the time of use can be coated by a known method for the key and the granule. In the case of an injection, a compound represented by the formula (1) or a physiologically acceptable salt thereof 161077.doc • 105-201245190 may be dissolved in water, and an isotonic agent may be dissolved as needed, and a pH may be added. Value modifiers, buffers and preservatives. These preparations may contain the compound of the present invention or a physiologically acceptable salt thereof in an amount of 0.01% by weight or more, preferably 5% to 7% by weight. In addition, such preparations may also contain other ingredients that are therapeutically effective. The compound of the present invention can enhance the effect thereof and an anti-obesity agent, a therapeutic agent for diabetes, a therapeutic agent for diabetic complications, an anti-hyperlipidemic agent, a blood pressure lowering agent, a diuretic, an anti-gout agent and the like (hereinafter, referred to as Used in combination for "concomitant use". The administration time of the compound of the present invention and the concomitant drug is not limited, and it may be administered to the subject at the same time, or may be administered by a time difference. Further, a combination of the compound of the present invention and a concomitant agent can also be prepared. The dosage of the pharmaceutical agent can be appropriately selected based on the amount of the clinical use. Further, the compounding ratio of the compound of the present invention and the concomitant agent can be appropriately selected depending on the administration target, the administration route, the target disease, the symptom, the combination, and the like. For example, when the administration target is a human, the compound of the present invention is used. For 1 part by weight, 0.01 to 100 parts by weight of a concomitant can be used. Further, in the anti-obesity agent, for example, as a central anti-obesity agent, there are mentioned: Dexfenfluramine, Fenfluramine, Phentermine, Topiramate, Anfei Bupropion, sibutramine, L〇rcaserin, Amfepramone, Dexamfetamine, Horse, Buza, Tesofensine, Phenyl Propylamine, Clobenzorex, Zonisamide, MCH (melanin-concentrating hormone) receptor antagonist (eg BMS-830216, etc.), nerve 16l077.doc -106 · 201245190 peptide Y5 receptor antagonist (eg, S-2367, etc.), neuropeptide Y2 receptor agonist (eg, AC-1 623 52, etc.), opioid μ receptor antagonist (eg, naltrexone, etc.), An opioid μ receptor inverse agonist (for example, GSK-1521498, etc.), a histamine Η3 receptor antagonist (for example, ΗΡΡ-404, etc.); and a peptide appetite suppressant (for example, Leptin) ), GLP-1 analogues (eg liraglutide) ), marijuana-like receptor antagonists (eg, TM38837, etc.), AgRP-aggregated proteins (AgRP, Agouti-related protein) inhibitors (eg, TTP-435, etc.), pancreatic lipase inhibitors (eg, Roche Fresh, New) Cetilistat, etc., glucokinase activator (eg AZD-5658, etc.), microsomal triglyceride transporter (MTP) inhibitor (eg JNJ-16269110, etc.), 醯Kytozyme A: dimercapto Glycerol thiotransferase (DGAT) inhibitor (eg, AZD-5658, etc.), sodium-dependent glucose donor (SGLT) 2 inhibitor (eg, Canagli Hozin, etc.), β3 agonist (eg, LY-377604, etc.), methyl sulfide An amine melamine peptidase (MetAP) 2 inhibitor (for example, ZGN-433 or the like), an 11β-based hydroxide steroid dehydrogenase type 1 (11PHSD1) inhibitor (for example, AZD-8329 or the like), and the like. Examples of the therapeutic agent for diabetes include an insulin preparation (for example, an animal insulin preparation extracted from a cow, a pancreas of a pig, a human insulin preparation synthesized by genetic engineering using Escherichia coli or yeast, zinc zinc, protamine zinc insulin, a fragment or derivative of insulin, an oral insulin preparation), an insulin resistance improving agent (for example, D-Pioglitazone or its hydrochloride, Rosigkitazone or its maleate, A Aleglitazar, ZYH1, Lobeglitazone, Balaglitazone, THR-0921, GFT-505, Indeglitazar, 161077.doc -107- 201245190

Siglitazar ' MBX-2044 ' MBX-102 ' INT-131 ' DSP-8658 , etc. ), a-glucosidase inhibitors (eg Voglibose, Acarbose, Miglitol) (Miglitol), emiglitate (Emiglitate, etc.), double veins (such as metformin, etc.), insulin secretion promoters (such as Tolbutamide, Glibenclamide, Gupeng vinegar (Gumpen vinegar) Gliclazide), Chlorpropamide, Tolazamide, Acetohexamide, Glyclopyramide, Glimepiride, Glipizide Is a sulfonylurea agent; Repaglinide, Nateglinide, Mitiglinide, etc., a dipeptidyl peptidase (DPP) IV inhibitor (eg sitagliptin (eg, sitagliptin) Sitagliptin), Vildagliptin, Saxagliptin, Linagliptin, Aglita, Alogliptin, Tenelegliptin, Anagliptin, Similar to Gemigliptin, Trelagliptin, GLP-1, GLP-1 (eg, Exenatide, Liraglutide, Albiglutide, Duraglutide, Lixisenatide, etc.), sodium-dependent glucose donor (SGLT) 2 inhibitors (eg Dapagliflozin, Canagliflozin, Empagliflozin, Ipragliflozin, Tofogliflozin, etc.), SGLT1 inhibitors (eg LX_4211, DSP-3235, etc.), 11β-hydroxide dehydrogenase! Type (llpHSDl) inhibitors (eg BMS-770767, INCB013739, LY2523199, etc.), glucokinase activators (eg ARRY-403, TTP399, etc.), glycogen phosphorylase inhibitors (eg GSK-1362885, etc.), 161077.doc -108- 201245190 Glucagon hormone receptor antagonists (such as LY2409021, ΜΚ-3577, etc.), GPR40 agonists (such as ΤΑΚ-875), and the like. Examples of the therapeutic agent for diabetic complications include aldose reductase inhibitors (for example, Epalrestat, Ranirestat, etc.), neurotrophic factors (for example, NGF, TAK-428, etc.), PKC (Protein Kinase C, protein kinase C) inhibitor (such as Ruboxistaurin Mesylate), AGE inhibitor (such as Pyridoxamine, etc.), active oxygen scavenger (such as lipoic acid, etc.) , cerebral vasodilators (such as Tiapride, Mexiletine, etc.), angiogenesis inhibitors (such as Defibrotide, Ranibizumab, etc.), Nrf2 activators ( For example, RTA-402, etc., endothelin antagonists (such as Atrasentan, etc.), phosphodiesterase inhibitors (such as PF-489791, etc.), CCR2 receptor antagonists (such as CCX-140, etc.), T-type calcium channel antagonist (for example, ABT-639, etc.), GABA (y-amino butyric acid, γ-aminobutyric acid) receptor modulator (for example, BMS-954561, etc.). As an anti-hyperlipidemic agent, HMG-CoA (P-hydroxy-p-methyl glutaryl-CoA, β-trans-β-methylglutarate monosaccharide coenzyme A) reductase inhibitor (for example, pravastatin) ;T (Pravastatin), Simvastatin, lovastatin, atorvastatin, fluvastatin, pitavastatin, rosuvastatin (Rosuvastatin) Or a salt thereof (for example, sodium salt, I bow salt), a Fibrate compound (for example, BezaHbrate, CloHbrate, SimHbrate, Klipbe) Clinofibrate, etc., anion exchange resin (for example, cholestene 161077.doc -109-201245190 amine (Colestyramine), etc.), cholesterol absorption inhibitor (such as Ezetimibe, etc.), Probucol (Probucol) ), acid-based agents (such as niacin (Niacin) and sustained release preparations), ethyl eicosapentaenoate, CETP (Cholesteryl Ester Transfer Protein) inhibitors (such as Ansai) Anacetrapib, Dalcetrapib ), ACAT (Acyl-CoA-Cholesterol Acyltransferase, A_ acyl coenzyme cholesterol acyl transferase) inhibitors (e.g., K604, etc.) and the like. As a blood pressure lowering agent, an angiotensin converting enzyme inhibitor (for example, Captopril, Enalapril, Alacepril, Delapril, Reino) Lisinopril, Imidapril, Benazepril, Cilazapril, Temocapril, Trandolapril, etc., blood vessels A gonadostatin II antagonist (eg, olmesartan Medoxomil, Candesartan cilexetil, Azilsartan Medoxomil, Losartan, Eprosartan) , Valsartan, Telmisartan, Irbesartan, Tasosartan, etc.;; bowing agent (eg Nicardipine Hydrochloride) , Manidipine Hydrochloride, Nisoldipine, Nitrididine, Nilvadipine, Amlodipine, etc., Renin inhibitors (eg Aliki (Aliskiren), etc., beta blockers (eg Atenolol, Bisoprolol, Betaxolol, Metoprolol, etc.), alpha blockers ( For example, Urapidil, Trafals 161077.doc -110- 201245190 Terazosin, Doxazosin, Bunazosin, etc., αβ blockers (eg ammonia) Amosulalol, Arotinolol, Labetalol, Carvedilol, etc., Clonidine, and the like. Examples of the diuretic include a xanthine derivative (for example, salicyl salicylate, calcium salicylate, etc.), and a thiophene preparation (for example, an ethylthiophene V, a cyclopentyl tillage, and a trisulfide Hydrogen thioculation, hydrofluoric sulfonate, phenylhydrazine hydrogen thiophene p well, pentafluoroazepine p well, Poly sold 11 well (Polythiazide), antimony gas well, etc., anti-alcodone preparations (eg Epp Epleenone, Spironolactone, Triamterene, etc., carbonate dehydratase inhibitors (such as Acetazolamide, etc.), gas amides (such as chloranil) Ketone, Mefruside, Indapamide, etc., Azosemide, isosorbide, uric acid, Pirtanide, Bumetanide Bumetanide), Furosemide, and the like. As an anti-gout agent, there are mentioned: Allopurinol, Probenecid, Colchicine, Benzbromarone, Febuxostat, and citrate Wait. The above-mentioned concomitant agents may be used in combination of two or more kinds in an appropriate ratio. When the compound of the present invention is used in combination with a concomitant agent, the amount of the agent to be used can be reduced within a safe range in consideration of side effects of the agent. Therefore, it is possible to prevent side effects caused by such agents from being safe. [Examples] 161077.doc-111-201245190 Hereinafter, the present invention will be specifically described by way of examples, but the present invention is not limited to the examples. In the examples and the reference examples, the following abbreviations are sometimes used.

Me : mercapto Et : ethyl Ph : phenyl

Boc : third butoxycarbonyl N : equivalent (for example, 2 N HCl represents 2 equivalents of hydrochloric acid) THF : tetrahydroanthracene

NaBH(OAc)3: sodium triethoxysulfonate (Boc) 20: di-tert-butyl dicarbonate

Cbz : benzyloxycarbonyl

Pd/C: carbon

Pt/C: Platinum Carbon HPLC: High Performance Liquid Chromatograph DMF: N,N-Dimercaptodecylamine DIEA : Ν,Ν-Diisopropylethylamine DMSO: Dimercaptopurine 1^: Moer Concentration (111〇1/1〇(eg, 2]^曱amine represents 2 111〇1/1^ of the guanamine solution) BSA: Bovine serum albumin palm 醯-CoA: palmitoyl coenzyme A NaOH: sodium hydroxide reference Example 1: 2-(Cyclohexylamino)-3-phenyl-5,6,7,8-tetrahydropyrido[4,3-161077.doc •112· 201245190 d]pyrimidine-4(3H)- Production of ketone hydrochloride [Chem. 73]

Step (1):

To the compound 1 (65.88 g), a 25% aqueous ammonia solution (660 mL) was added, and the mixture was heated under reflux for 2 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was separated. The organic layer was combined and dried over anhydrous sodium sulfate and evaporated. The obtained residue was purified by a ruthenium column chromatography (Jiyuan/ethyl acetate = 5/3) to recrystallize the obtained crude product (hexane/diethyl ether = 9/1). Compound π(37 67 g) 0 MS-APCI: m/z: 271 ([M+H]+) 〇 'H-NMR (400 MHz, DMSO-d6) : δ (ppm) = 7.00 (br.s 2H) ) 4.05 (q, J-7.1, 2H), 3.92 (s, 2H), 3.37 (t, J=6.05 2H) 2 26 (t, J=6.0, 2H), 1.40 (s, 9H), 1.18 (t , J = 7.1, 3H). Step (ii) · Adding isothiocetic acid benzene vinegar (Hi mL) to a solution of compound 11 (19.3 g) in a bite (165 mL), heating and stirring overnight at 90 t; decompressing the reaction mixture After concentration, 'benzene was added and concentrated under reduced pressure. After washing the obtained crude crystals with diethyl ether - 161077.doc • 113· 201245190, the compound III (26 75 was obtained. The compound III was not further purified and used in the next reaction. Step (iii): at 〇 ° C Add 1,8-diazabicyclo[5.4.〇]-7-undecene (10.6 mL) to a solution of compound 111 (26.75 g) and hydrazine-dihydrazinamide (320 mL) and Ethyl methane (4.9 mL). The reaction mixture was stirred and stirred for 5 hours, then quenched with saturated aqueous sodium hydrogen carbonate, and extracted with di-methane. The organic layer was washed with water and dried over anhydrous sodium sulfate. After that, the residue was concentrated under reduced pressure. After the residue obtained was purified by chromatography on silica gel column chromatography (H.sub.s./ethyl acetate=3/1), Compound IV (22 〇3. !H-NMR (400 MHz) was obtained. , DMSO-d6) : δ (ppm) = 7.52-7.57 (m, 3H), 7.34-7.37 (m, 2H), 4.17 (s, 2H), 3.61 (t, J=5.8, 2H), 2.65 (t , J=5.7, 2H), 2.39 (s, 3H), 1.43 (s, 9H). Step (iv): Add anhydrous sulfuric acid to a solution of compound IV (5.0 g) in dioxane (1 mL) Town (20 g) and sodium acetate (2.31 g) ^ mix the reaction After cooling to -70 C, a solution of m-benzoic acid (9.89 g) in methane (15 mL) was added dropwise. The reaction mixture was stirred at -70 for 3.5 hours and then added at -30 &lt; The reaction was quenched with an aqueous solution of sodium thiosulfate, followed by extraction with dioxane. The organic layer was washed sequentially with a 10% aqueous sodium thiosulfate solution and a saturated aqueous solution of sodium hydrogencarbonate. Concentration under reduced pressure was carried out to thereby obtain Compound V (6.15 g). Compound v was used without further purification for the next reaction. Step (v): 161077.doc • 114· 201245190 to compound V (980 mg) &lt;» alkane (19 mL) solution was added cyclohexylamine (499 mg), diisopropylethylamine (977 mg) and 4-didecylamino group to bite (0.03 g) ' at 50 ° C The mixture was heated and stirred for 15 hours. Water was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. , Concentrated under reduced pressure by means of a gel column chromatography (hexane / ethyl acetate = 1 / 1) After purification of the obtained residue, compound VI (630 mg) was obtained. <H-NMR (400 MHz, CDC13): δ (ppm) = 7.43-7.52 (m, 3H), 7.16-7.22 (m, 2H), 4.22 (s, 2H), 3.81 (s, 2H), 3.55 (t, J = 5.8, 2H), 2.54 (s, 2H), 1.97-1.98 (m, 2H), 1.47-1.56 (m, 3H), 1.41 (s, 9H), 1.25_1.33 (m, 2H), 0.92-1.06 (m, 3H). Step (vi): To a solution of Compound VI (630 mg) in dioxane (5 mL) was added EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 2 hr. 'H-NMR (400 MHz, DMSO-d6): δ (ppm) = 7.63-7.68 (m 3H), 7.38-7.40 (m, 2H), 4.01 (s, 2H)' 3.37-3.38 (m,1H) 3.56-3.59 (m, 2H), 3.01-3.12 (m, 2H), 1.87-1.90 (m, 2H) 1.73-1.76 (m, 2H), 1.62-1.66 (m, 1H), 1.32-1.42 (m, 4H) 1.09-1.12 (m, 1H). Example 1 : 3-{[2·(Cyclohexylamino)-4-oxo-3-phenyl-3,5,7,8·tetrahydropyrido[4,3-d]pyrimidine-6 (4Η)-yl]carbonyl}azetidinic acid third I6l077.doc •115· 201245190 manufacture of butyl ester [化74]

To a solution of compound VII (360 mg) in N,N-dimethylformamide (5 mL) was added 1-(T-butoxy-reactive) azetidin-3-3 decanoic acid (2 01 mg) , triethylamine (0.416 mL), 1-hydroxybenzotriazole (405 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (619) Mg). After reacting the reaction mixture for 15 hours at 25 C, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was applied to ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the residue obtained was purified by a silica gel column chromatography (ethyl acetate), the compound of Example 1 (335 mg) was obtained. 'H-NMR (400 MHz, DMSO-d6) : δ (ppm) = 7.50-7.59 (m, 3H), 7.25-7.27 (m, 2H), 5.03-5.09 (m, 1H), 3.68-4.18 (m , 9H), 3.49 (t, J = 5.8 Hz, 1H), 2.45-2.51 (m, 2H), 1.67-1.69 (m, 2H), 1.49-1.56 (m, 3H), 1.36-1.37 (m, 9H ), 0.95-1.26 (m, 5H). Example 2: 6-(azetidin-3-ylcarbonyl)-2-(cyclohexylamino)_3_phenyl-S,6,7,8-tetrahydropyridindole 4,3_d]pyrimidine _4(3H)_Manic acid production [Chem. 75] I61077.doc -116- 201245190

To a solution of the compound of Example 1 (270 mg) in 1,4-dioxane (4 mL), 4 mol/L of dioxane hydrochloride (4 mL), and the mixture was stirred at 25 ° C for 1 hour. After concentration under reduced pressure, Example Compound 2 (330 mg) was obtained. ^-NMR (400 MHz, DMSO-d6): δ (ppm) = 7.53-7.60 (m, 3H), 7.27-7.30 (m, 2H), 4.01-4.45 (m5 l〇H), 3.50-3.58 (m , 2H), 2.58-2.72 (m, 2H), 1.66-1.73 (m, 2H), 1.47-1.58 (m, 3H), 0.99-1.30 (m, 5H). Example 3: 6-[(l-Benzylazetidin-3-yl)carbonyl]-2-(cyclohexylamino)-3-phenyl-5,6,7,8-tetrahydropyridine And [4,3-d]pyrimidine-4(3H)-辋 manufacture [Chem. 76]

To a solution of Example Compound 2 (330 mg) in N,N-dimethylamine (5 mL), bromophenylbenzene (0.065 mL) and diisopropylethylamine (0.33 mL). After the reaction mixture was stirred at 25 ° C for 16 hours, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After the residue of 161077.doc -117-201245190 obtained was purified by a ruthenium column chromatography (methanol/methanol = 5/95), Example Compound 3 (98 mg) was obtained. H-NMR (400 MHz, DMSO-d6): δ (ppm) = 7.51-7.58 (m, 3H), 7.21-7.32 (m, 7H), 5.01-5.06 (m, 1H), 3.32-4.16 (m , 10H), 3.15-3.19 (m, 2H), 2.44 - 2.50 (m, 2H), 1.66-1.69 (m, 2H), 1.47-1.54 (m, 3H), 0.99.1.23 (m, 5H). Examples 4 to 16: According to the method of Example 3, the compounds of Examples 4 to 16 were synthesized using the Example Compound 2 synthesized in Example 2. [化77]

[Table 1] 161077.doc 118-201245190 Example No. R3 Ή-NMR spectrum 4 Fxr iH-NMR (400 MHz, CD3OD): 5{ppm) = 7.45-7.54 (m, 3H), 7.15-7.24 (m, 4H) ), 6.90-6.97 (m, 2H), 4.26 (s, 1H), 4.05 (s, 1H), 3.72-3.82 (m, 2H), 3.43-3.58 (m, 6H), 3.24-3.31 (m, 2H) ), 2.51-2.56 (m, 2H), 1.70-1.73 (m, 2H), 1.44-1.52 (m, 3H), 1.18-1.24 (m, 2H), 0.97-1.04 (m, 3H). 5 iH- NMR (400MHz, CD3OD): 5 (ppm) = 7.47-7.54 (m, 3H), 7.21-7.24 (m, 1H), 7.15-7.18 (m, 2H), 6.96-7.03 (m, 2H), 6.87- 6.90 (m, 1H), 4.26 (s, 1H), 4.05 (s, 1H), 3.79-3.80 (m, 1H), 3.72-3.75 (m, 1H), 3.49-3.55 (m, 6H), 3.25- 3.33 (m, 2H), 2.53-2.57 (m, 2H), 1.70-1.73 (m, 2H), 1.48-1.52 (m, 3H), 1.18-1.24 (m, 2H), 1.00-1.05 (m, 3H 6 iH-NMR (400MHz, CD30D): 6 (ppm) = 7.60-7.61 (m, 3H), 7.25-7.32 (m, 6H), 4.35 (s, 1H), 4.14 (s, 1H), 3.89 -3.90 (m, 1H), 3.82-3.85 (m, 1H), 3.57-3.63 (m, 6H), 3.38-3.44 (m, 2H), 2.61-2.66 (m, 2H), 1.80-1.83 (m, 2H), 1.54-1.62 (m, 3H), 1.31-1.34 (m, 2H), 1.09-1.14 (m, 3H). 7 Λχ· iH-NMR (400MHz, CD3OD):. 5(ppm)= 7.51- 7.53 (m, 3H ), 7.15-7.20 (m, 6H), 4.26 (s, 1H), 4.06 (s, 1H), 3.76-3.85 (m, 1H), 3.72-3.75 (m, 1H), 3.48-3.55 (m, 6H) ), 3.25-3.33 (m, 2H), 2.50-2.60 (m, 2H), 1.70-1.78 (m, 2H), 1.42-1.52 (m, 3H), 1.18-1.28 (m, 2H), 0.95-1.05 (m, 3H). 8 N〇xr iH-NMR (400MHz, CD3OD): 6 (ppm) = 7.59-7.72 (m, 5H), 7.49-7.53 (m, 4H), 7.27-7.30 (in, 2H) , 4.38 (s, 1H), 4.17 (s, 1H), 3.91-3.92 (m, 1H), 3.84-3.87 (m, 1H), 3.72-3.74 (m, 2H), 3.59-3.67 (m, 4H) , 3.33-3.46 (m, 2H), 2.63-2.68 (m, 2H), 1.82-L85 (m, 2H), 1.56-1.64 (m, 3H), 1.30-1.35 (m, 2H), 1.07-1.20 ( m, 3H). 9 NCXX^ iH-NMR (400MHz, CD3OD): 6(ppm) = 7.51-7.70 (m, 7H), 7.23-7.21 (m, 2H), 4.37 (s, 1H), 4.16 (s , 1H), 3.85-3.89 (m, 2H), 3.60-3.70 (m, 6H), 3.38-3.43 (m, 2H), 2.64-2.65 (m, 2H), 1.81-1.84 (m, 2H), 1.59 -1.62 (m, 3H), 1.29-1.38 (m, 2H), 1.10-1.13 (m, 3H). 10 HO^ iH-NMR (400MHz, CD3OD): 6(ppra)= 7.99-8.02 (m, 2H ), 7.59-7.65 (m, 3H), 7.45-7.50 (m, 2H), 7.26-7.30 (m, 2H), 4.40 (s, 1H), 4.17 (s, 1H), 3.88-4.14 (m, 8H) ), 3.62-3.67 (m, 1H), 2.67-2.70 (m, 2H), 1.70-1 .78 (m, 2H), 1.55-1.68 (m, 3H), 1.30-1.42 (m, 2H), 1.08-1.18 (m, 3H). 161077.doc •119- 201245190 11 iH-NMR (400MHz, CD3OD ): 6 (ppm) = 8.04 (d, J = 28.4 Hz, 1H), 7.86-7.89 (m, 1H), 7.43-7.51 (m, 4H), 7.32-7.33 (m, 1H), 7.13-7.17 ( m, 2H), 4.27 (s, 1H), 3.98-4:14 (m, 7H), 3.74-3.79 (m, 2H), 3.48-3.59 (m, 1H), 2.53-2.56 (m, 2H), 1.70-1.72 (m, 2H), 1.47-1.51 (m, 3H), 1.18-1.23 (m, 2H), 0.99-1.02 (m, 3H). 12 jQT&quot; iH-NMR (400MHz, CD3OD): 5( Ppm) = 7.47-7.54 (m, 3H), 7.15-7.18 (m, 2H), 7.01-7.03 (m, 1H), 6.58-6.66 (m, 3H), 4.26 (s, 1H), 4.06 (s, 1H), 3.78-3.83 (m, 1H), 3.73-3.76 (m, 1H), 3.44-3.54 (m, 6H), 3.21-3.31 (m, 2H), 2.53-2.55 (m, 2H), 1.71- 1.74 (m, 2H), 1.49-1.52 (m, 3H), 1.19-1.25 (m, 2H), 1.00-1.05 (m, 3H). 13 Η0ΧΧ&quot; iH-NMR (400MHz, CD3〇D): 5( Ppm) = 7.47-7.52 (m, 3H), 7.17-7.18 (m, 2H), 6.98-7.03 (m, 2H), 6.61-6.64 (m, 2H), 4.26 (s, 1H), 4.05 (s, (H, 2H) 1.53 (m, 3H), 1.18-1 .28 (m, 2H), 0.98-1.05 (m, 3H). 14 cr iH-NMR (400MHz, CD3〇D): 5 (ppm) = 8.35-8.90 (m, 1H), 7.70-7.72 (m, 1H), 7.47-7.54 (m, 3H), 7.32-7.35 (m, 2H), 7.17-7.22 (m, 3H), 4.27 (s, 1H), 4.07 (s, 1H), 3.73-3.81 (m, 2H), 3.52-3.68 (m, 6H), 3.37-3.40 (m, 2H), 2.53-2.56 (m, 2H), 1.71-1.74 (m, 2H), 1.49-1.53 (m, 3H), 1.19- 1.25 (m, 2H), 1.00-1.05 (m, 3H). 15 cr iH-NMR (400MHz, CD3OD): 5 (ppm) = 8.34-8.41 (m, 2H), 7.70-7.72 (m, 1H), 7.47-7.54 (m, 3H), 7.31-7.32 (m, 1H), 7.16-7.18 (m, 2H), 4.27 (s, 1H), 4.06 (s, 1H), 3.73-3.76 (m, 2H), 3.50-3.60 (m, 6H), 3.29-3.36 (m, 2H), 2.53-2.56 (m, 2H), 1.71-1.74 (m, 2H), 1.49-1.53 (m, 3H), 1.19-1.25 (m , 2H), 1.00-1.05 (m, 3H). 16 iH-NMR (400MHz, CD3OD): 6{ppm) = 8.35-8.38 (m, 2H), 7.47-7.52 (m, 3H), 7.27-7.30 ( m, 2H), 7.15-7.18 (m, 2H), 4.27 (s, 1H), 4.06 (s, 1H), 3.73-3.81 (m, 2H), 3.52-3.62 (m, 6H), 3.31-3.34 ( m, 2H), 2.53-2.56 (m, 2H), 1.71-1.74 (m, 2H), 1.49-1.53 (m, 3H), 1.19-1.25 (m, 2H), 1.00-1.05 (m, 3H). Reference Example 2: 2-(cyclohexylsulfanyl)-4-oxo-3 Manufacture of -phenyl-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-carboxylic acid tert-butyl ester [Chem. 78] 161077.doc •120· 201245190

Step (X): To a solution of compound 111 (5.64 g) in N,N-dimethylformamide (6 mL) was added '1,8-diazabicyclo[5.4.0]-7- Alkene (2.28 g) and iodocyclohexane (3.50 g). After the reaction mixture was stirred at 40 ° C for 20 hours, the reaction was quenched with EtOAc EtOAc EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and evaporated. After the residue obtained was purified by a Shih-Hybrid column chromatography (hexanes / ethyl acetate = 4/1), Compound VIII (4.15 g) was obtained. !H-NMR (400 MHz, DMSO-de) : δ (ppm) = 7.50-7.53 (m, 3H), 7.21-7.26 (m, 2H), 4.34 (s, 2H), 3.73-3.79 (m, 1H ), 3.68- 3.71 (m, 2H), 2.70-2.72 (m, 2H), 1.98-2.05 (m, 2H), 1.68- 1.72 (m, 2H), 1.55-1.60 (m, 1H), 1.48 (s , 9H), 1.34-1.42 (m, 4H), 1.23-1.28 (m, 1H). Example 17: 6-[(l-Benzylazetidin-3-yl)carbonyl]·2·(cyclohexylsulfanyl)-3_phenyl-5,6,7,8-tetrahydro Manufacture of pyrido[4,34]pyrimidin-4(311)-one [Chem. 79]

161077.doc • 121 - 201245190

Steps (xi) to (xiv) were carried out in accordance with Reference Example 1 and the procedures (vi) to (ix) of the examples to obtain the compound of Example 17. H-NMR (400 MHz, DMSO-d6): δ (ppm) = 7.50-7.56 (ms 3H), 7.19-7.32 (m, 7H), 4.26 (s, 1H), 4.08 (s, 1H), 3.37 -3.75 (m, 8H), 3.19 (t, J=7.36 Hz, 2H), 2.59-2.63 (m, 2H), 1.91-1.96 (m, 2H), 1.47-1.65 (m, 3H), 1.13-1.39 (m, 5H) ° Example 18: 6-[(l-Benzylazetidin-3-yl)carbonyl]-2-indolyl-3-phenyl-5,6,7,8-tetra Manufacture of hydropyrido[4,3-|1]pyrimidin-4(311)-one [Chem. 80]

Step (XV): Cool a solution of compound V (780 mg) in tetrahydrofuran (1 mL) to -78 ° C under nitrogen, and add 2 mol/L of pentylmagnesium bromide in diethyl ether (1.0 mL). . After the reaction mixture was stirred at jfc for 1 hour, a saturated aqueous gasification solution was added and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. 161077.doc -122- 201245190 After the residue obtained was purified by a ruthenium column chromatography (hexane/ethyl acetate == 丨/丨), Compound XII (385 mg) was obtained. H-NMR (400 MHz, DMSO-dg): δ (ppm) = 7.48-7.57 (m, 3H), 7.34-7.36 (m, 2H), 4.16 (s, 2H), 3.60 (t, J = 5.7 Hz , (2, H), 2. 4H), 0.75 (t, J = 7.0 Hz, 3H). Steps (xvi) to (xix) were carried out according to the reference examples i and the steps (vi) to (ix) of Example u to obtain the compound of Example 18. JH-NMR (400 MHz, CD3OD): δ (ppm) = 7.52-7.60 (m, 3H), 7.24-7.34 (m, 7H), 4.44 (s, 1H), 4.23 (s, 1H), 3.87 (t , J=5.9 Hz, 1H), 3.57-3.70 (m, 6H), 3.36-3.43 (m, 2H), 2.74-2.76 (m, 2H), 2.33-2.37 (m, 2H), 1.55-1.59 (m , 2H), 1.18-1.42 (m, 4H), 0.80 (t, J = 6.8 Hz, 3H). Reference Example 3: 6-(azetidin-3-ylcarbonyl)_2-(cyclohexylsulfanyl)-3-phenyl-5,6,7,8-tetrahydro*pyridinyl[4,3 -d] Manufacture of mouth bite-4(3H)-ketone trifluoroethylene salt [Chem. 81]

Eight AVI Toluene (1 〇 mL) was added to Compound X (524 mg), and the mixture was stirred under ice-cooling. Further, trifluoroacetic acid (5 mL) was added, and -123·16l077.doc 201245190 was allowed to stand at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to give compound XVI (630 mg). Example 19: (2E)-M4-[(M[2-(cyclohexylsulfanyl)-4)oxo_3_phenyl-3,5,7,8-tetrahydropyrido[4,3 -d]pyrimidinyl]carbonyl}azetidin-1-yl)methyl]phenyl}propan-2-enoate methyl ester production [Chem. 82]

To a solution of the compound XVI (135 mg) in di-methane (2 mL), (3-(4-methyl-bromophenyl)acrylic acid (E)-decyl ester (47 mg) and diisopropylethylamine (0.050) (mL), after stirring at 25 ° C for 30 minutes under a nitrogen atmosphere, NaBH(OAc) 3 (53 mg) was added. After the reaction mixture was stirred at 25 ° C for 15 hours, a saturated aqueous solution of ammonium sulfate was added, and the mixture was extracted with EtOAc. After the residue obtained was purified by a silica gel column chromatography (methanol/methanol: 1/10), the compound 19 (34 mg) was obtained. MS (M+H+) = 599 Example 20: (2E)-3-{4-[(3-{[2-(cyclohexylsulfanyl)-4-oxo-3-phenyl-3,5 ,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}propane-2·diluted acid Manufacturing [Chem. 83] 161077.doc •124· 201245190

Mol / L sodium hydroxide aqueous solution mL). The reaction mixture was searched at 50 ° C; after stirring for 45 minutes, it was neutralized with a 1 mol/L aqueous hydrochloric acid solution and concentrated under reduced pressure. After the residue obtained was purified by a silica gel column chromatography (methanol/chloroform: 1/10), the compound of Example 20 (12 mg) was obtained. H-NMR (400 MHz, DMSO-d6): δ (ppm) = 7.65-7.52 (m, 6H), 7.34-7.27 (m, 4H), 6.52-6.47 (m, 1H), 4.26-3.24 (m , 10H), 2.68-2.59 (m, 2H), 1.97-1.90 (m, 2H), 1.60-1.15 (m, 10H) 〇Examples 21 to 75 ·· According to Example 3, Example 17, Example I9 Alternatively, the compounds of Examples 21 to 75 were synthesized by the method of Example 20. [化84]

161077.doc -125· 201245190 Example No. X Ri R2 R3 Ή-ΝΜΙΙ map 21 NH Ph ό iH-NMR (400 MHz, CD3OD): 6 (ppm) = 7.54-7.63 (m, 3H), 7.14-7.28 (m , (6,6H), 4.35 (s, 1H), , 2H), 2.58-2.66 (m, 4H), 1.75-1,83 (m, 2H), 1.51-1.62 (m, 3H), 1.25-1.37 (m, 3H), 1.03-1.19 (m, 3H) 22 • NH Ph ό H〇2Cnx 43 ^ ..^coint^corocNCTiON 5° α β^σ&gt;σ»ν〇ι〇〇〇ν〇Γ〇·-· g out of seven CO &lt;N CM (N d Η H »«1 〇H|H 1 1 1 1 1 1 1 1 0 5cnoocnooo 0010 inch (Ο τ-Η 〇0 〇0 ν〇^ 0〇L〇CN Ο ψ ρ ίη w CO κ 卜卜寸HdCitNCSICMCOCOCO 23 NH Ph ό H〇2Cnx Ή-ΝΜΙ^ΟΟΜΗζ, CD3OD): 5(ppm)= 7.65-7.52 (ra, 6H), 7.34-7.27 (m, 4H), 6.52-6.47 (m, 1H), 4.26 -3.24 (m, 10H), 2.68-2.59 (m, 2H), 1.97-1.90 (m, 2H), 1.60-1.15 (m, 10H). 161077.doc 126· 201245190 24 NH Ph ό Me02C^^ iH- NMR (400MHz} CD3OD): 6 (ppm) = 7.95-7.90 (m, 2H), 7.67-7.54 (m, 3H), 7.34 (t, J = 8.0 Hz, 2H), 7.28-7.26 (m, 2H) , 4 .35 (s, 1H), 4.15 (s, 1H), 3.93-3.54 (m, 8H), 3.35-3.25 (m, 2H), 2.75-2.60 (m, 6H), 1.86-1.81 (m, 2H) , 1.64-1.52 (m, 3H), 1.37-1.28 (m, 3H), 1.19-1.07 (m, 3H). 25 NH Ph ό H〇2CiX^ iH-NMR (400MHz, CD3OD): 5(ppm)= 7.89 (d, J = 8.0 Hz, 2H), 7.64-7.55 (m, 3H), 7.30-7.25 (m, 4H), 4.36 (s, 1H), 4.15-4.06 (m, 3H), 3.98-3.84 ( m, 5H), 3.62-3.59 (m, 1H), 3.26-3.22 (m, 2H), 2.89-2.84 (m, 2H), 2.68-2.62 (m, 2H), 1.85-1.80 (m, 2H), 1.62-1.54 (m, 3H), 1.37-1.28 (m, 3H), 1.17-1.07 (m, 3H). 26 NH Ph ό F iH-NMR (400MHz, CD3OD): 5 (ppm) = 7.64-7.55 ( m, 3H), 7.33-7.25 (m, 3H), 7.09-7.03 (m, 2H), 4.37 (s, 1H), 4.15 (s, 1H), 3.94-3.75 (m, 9H), 3.62 (brt, 1H, J = 6.0 Hz), 2.93-2.89 (m, 2H), 2.67-2.62 (m, 2H), 2.56-2.52 (m, 2H), 1.83-1, 80 (m, 2H), 1.63-1.55 ( m, 3H), 1.37-1.28 (m, 2H), 1.16-1.07 (m, 3H). 161077.doc 127- 201245190 27 NH Ph ό Cl Ή-ΝΜΙ?(400ΜΗζ, CD3OD): 5(ppm)= 7.64 -7.55 (m, 3H), 7.37-7.33 (m, 2H), 7.28-7.25 (m, 2H), 7.22-7.19 (m, 1H), 4.37 (s, 1H), 4.15 (s, 1H), 3.99 (brd, 2H, J = 4.4 H z), 3.93-3.73 (m, 7H), 3.62 (brt, 1H, J = 5.8 Hz), 2.91-2.87 (m, 2H), 2.67-2.62 (m, 2H), 2.57-2.52 (m, 2H) , 1.83-1.80 (m, 2H), 1.63-1.55 (m, 3H), 1.37-1.28 (m, 2H), 1.16-1.07 (m, 3H). 28 NH Ph ό OMe iH-NMR (400MHz, CD3OD) : 5{ppm) = 7.65-7.55 (m, 3H), 7.31-7.25 (m, 3H), 6.99-6.98 (m, 1H), 6.91-6.88 (m, 1H), 4.39 (s, 1H), 4.33 -4.24 (m, 5H), 4.14 (s, 1H), 4.11-4.00 (m, 1H), 3.91-3.86 (m, 5H), 3.64-3.61 (m, 1H), 2.96-2.92 (m, 2H) , 2.70-2.64 (m, 2H), 2.56-2.51 (m, 2H), 1.83-1.80 (m, 2H), 1.63-1.55 (m, 3H), 1.37-1.28 (m, 2H), 1.16-1.08 ( m, 3H). 161077.doc 128- 201245190 iH-NMR (400MHz, CD3OD): 5 (ppm) = 29

NH

Ph

H02C

7.64-7.55 (m, 3H) 7.28-7.25 (m, 2H) 7.21-7.17 (m, 1H) 7.11-7.06 (m, 2H) 4.38 (s, 1H), 4.15 (s 1H), 3.99-3.79 (m 9H), 3.62 (brt, 1H, J 5.8 Hz), 2.88-2.83 (m 2H), 2.68-2.63 (m, 2H), 2.51-2.47 (m, 2H), 2.35-2.33 (m, 3H), 1.83 -1.80 (m, 2H), 1.63-1.55 (m, 3H), 1.37-1.28 (m, 2H), 1.16-1.07 (m, 3H). 30

NH

Ph

Ho2c

Ή-ΝΜΚ (400ΜΗζ, CD3OD): 6(ppm) = 7.67-7.55 (m, 3H) 7.30-7.25 (m, 3H) 7.10-7.05 (m, 2H) 4.37 (s, 1H), 4.14 (s 1H) , 3.93-3.67 (m 9H), 3.61 (brt, 1H, J = 5.8 Hz), 2.95-2.90 (m 31

NH

Ph

2H), 2H), 2H), 2H), 2.67-2.62 2.55-2.50 1.83-1.80 1.63-1.55 (m (m (m 3m), 1.37-1.28 2H), 1.16-1.07 3H). (m, (m, iH-NMR (400MHz, DMSO-de): 5 (ppm) = 7.53-7.59 (m, 5H), 7.25-7.29 (m, 2H), 6.49-6.53 (m, 2H), 5.06-5.12 ( m, 1H), 4.02-4.21 (m, 8H), 3.80-3.90 (m, 1H), 3.72-3.76 (m, 1H), 3.56-3.59 (m, 1H), 1.68-1.71 (m, 2H), 1.48-1.60 (m, 3H), 1.16-1.25 (m, 4H), 0.97-1.05 (m, 1H). 161077.doc 129- 201245190 32 NH F ό (X iH-NMR(400MHz, CD3OD): 5( Ppm) = 7.47-7.51 (m, 1H), 7.15-7.32 (m, 8H), 4.24-4.28 (m, 1H), 4.06 (s, 1H), 3.83-3.84 (m, 1H), 3.72-3.75 ( m, 1H), 3.47-3.60 (m, 6H), 3.31-3.35 (m, 2H), 2.52-2.57 (m, 2H), 1.71-1.74 (m, 2H), 1.48-1.58 (m, 3H), 1.19-1.25 (m, 2H), 1.07-1.10 (m, 3H). 33 NH ό iH-NMR (400MHz, CD3OD): 5(ppm) = 7.63-7.65 (m, 1H), 7.34-7.40 (m , (6,6H) ), 1.80-1.90 (m, 2H), 1.58-1.71 (m, 3H), 1.27-1.40 (m, 2H), 1.15-1.22 (m, 2H). 34 NH ^aF ό iH-NMR (400MHz, CDCI3) ): 5 (ppm) = 7.11-7.23 (m, 9H), 4.34 (s, 1H), 4.06 (s, 1H), 3.75-3.82 (m, 3H), 3.39-3.67 (in, 5H), 3.27- 3.30 (m, 2H), 2.48-2.55 (m, 2H), 1.94 (bs, 1H), 1.79-1.83 (m, 2H), 1.49-1.52 (m, 3H), 1.07-1.36 (m, 5H). 161077.doc 130. 201245190 Ή-ΝΜΙ?(400ΜΗζ, cd3〇d): δ(ρρπχ)= 8.01-7.99 (m, 1H), 7.89-7.94 (m, 1H), 7.72-7.77 (m, 1H), 7.51-7.54 (m, 1H), 7.30-7.33 (m, 5H), 4.39-4.41 (m, 1H), 4.19-4.20 (m, 1H), 4.00-4.02 (m, 1H), 3.86-3.90 (m , 1H), 3.66-3.72 (m, 6H), 3.44-3.49 (m, 2H), 2.68-2.70 (m, 2H), 1.78-1.95 (m, 2H), 1.58-1.78 (m, 3H), 1.07 -1.42 (m, 5H). 35 NH Λ CN u 36 NH 0 0 NH ό

iH-NMR (400MHz, CD3OD): 6 (ppm) = 7.95-7.97 (m, 1H), 7.75-7.82 (m, 2H), 7.62 (bs, 1H), 7.50-7.51 (m, 5H), 4.35- 4.41 (m, 7H), 4.17 (bs, 2H), 3.93-4.00 (m, 2H), 3.66 (bs, 1H), 2.68-2.75 (m, 2H), 1.62-1.89 (m, 5H), 1.11- 1.37 (m, 5H). Ή-ΝΜΚ (400ΜΗζ, CD3OD): 5(ppm) = 7.81 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.3 Hz, 2H), 7.20-7.24 (m , 5H), 4.36 (s, 1H), 4.06 (s, 1H), 2.52-2.56 (m, 2H), 1.80-1.83 (m, 2H), 1.50-1.53 (m, 3H), 1.19-1.35 (m , 2H), 1.02-1.11 (m, 3H). 161077.doc 131 - 201245190 38 NH j〇ό iH-NMR (400MHz, CD3OD): δ (ppm 8.81-8.72 (m, 1H), 8.47 (bs, 1H), 7.78-7.86 (m, 1H), 7.67-7.69 (m, 1H), 7.34-7.36 (m, 5H), 4.38 (s, 1H), 4.17 (s, 1H), 3.90-4.05 (m, 1H), 3.80-3.89 (m, 1H), 3.70-3.78 (xn, 4H), 3.50-3.77 (m, 4H), 2.66-2.68 (m, 2H), 1.88-1.92 (m, 2H), 1.55- 1.76 (m, 3H), 1.07-1.45 (m, 5H). 39 NH A ό (X iH-NMR (400MHz, CD3OD): 5 (ppm) = 7.39-7.40 (m, 5H), 4.35 (s, 1H ), 4.13 (s, 1H), 3.76-3.97 (m, 9H), 3.56-3.59 (m, 1H), 2.64-2.66 (m, 1H), 2.54-2.60 (m, 2H), 2.00 (bs, 2H) ), 1.81 (bs, 2H), 1.68-1.71 (m, 1H), 1.38-1.41 (m, 4H), 1.20-1.32 (m, 4H), 0.78 (bs, 2H). 40 NH ό (X iH-NMR (400MHz, CD3OD) ): δ (ppm) = 7.28-7.33 (m, 5H), 4.40-4.50 (m, 1H), 4.32 (s, 1H), 4.09 (s, 1H), 3.83-3.94 (m, 1H), 3.76- 3.80 (m, 1H), 3.38-3.41 (m, 2H), 2.58-2.68 (m, 2H), 2.50-2.57 (m, 2H), 2.30-2.40 (m, 2H), 1.92-2.02 (m, 2H ), 1.61-1.80 (m, 5H), 1.12-1.42 (m, 6H). 132-161077.doc 201245190 41 NH ό (X iH-NMR (400MHz, CD3OD): 5(ppm) = 7.28-7.33 (m , 5H), 4.35 (s, 1H), 4.20-4.30 (m, 1H), 4.14 (s, 2H), 4.00-4.10 (m, 1H), 3.88-3.90 (m, 2H), 3.78-3.80 (m , 2H), 3.58-3.65 (m, 6H), 3.39-3.41 (m, 2H), 2.56-2.58 (m, 2H), 2.02-2.12 (m, 1H), 1.91-1.97 (m, 4H), 1.71 -1.81 (m, 2H), 1.55-1.68 (m, 2H), 1.20-1.45 (m, 6H). 42 NH Cl ό Ou DMSO-d^: 6 (ppm) = 7.71-7.66 (m, 1H), 7.58-7.48 (m, 2H), 7.41-7.36 (m, 1H), 7.33-7.19 (m, 5H), 5.64-5.58 (m, 1H), 4.16-3.30 (m, 10H), 3.21-3.14 (m , 2H), 2.51-2.45 (m, 2H), 1.66-1.50 (m, 5H), 1.28-0.92 (m, 5H). 43 NH Ph A c,iX 】H-NMR (400MHz, CD3OD): δ ( Ppm)= 7.58-7.60 (m , 3H), 7.33-7.35 (m, 4H), 7.24 (bs, 2H), 4.39 (s, 1H), 3.87 (s, 1H), 3.85-3.89 (m, 1H), 3.65-3.78 (m, 6H ), 3.42-3.55 (m, 2H), 2.68-2.72 (m, 3H), 0.71-0.73 (m, 2H), 0.44 (bs, 2H). 161077.doc 133- 201245190 44 NH Ph 4 (X iH- NMR (400MHz, CD3OD): δ(ρρπχ) = 7.57-7.61 (m, 3H), 7.23-7.31 (m, 7H), 4.43-4.47 (m, 1H), 4.36 (s, 1H), 4.13 (s, 1H), 3.81-3.83 (m, 2H), 3.59-3.66 (m, 6H), 3.41-3.43 (m, 2H), 2.61-2.63 (m, 2H), 2.22-2.23 (m, 2H), 1.81- 1.83 (m, 2H), 1.63-1.65 (m, 2H). 45 NH Ph Clxx iH-NMR (400MHz, CD3OD): 5 (ppm) = 7.57-7.60 (m, 3H), 7.23-7.31 (m, 6H) ), 4.43-4.45 (m, 1H), 4.34 (s, 1H), 4.13 (s, 1H), 3.81-3.83 (m, 2H), 3.57-3.63 (m, 6H), 3.37-3.40 (m, 2H) ), 2.61-2.63 (m, 2H), 2.22-2.23 (m, 2H), 1.82-1.83 (m, 2H), 1.63-1.65 (m, 2H). 46 NH Ph ό &gt;H-NMR (400MHz, DMSO-i}: 5 (ppm) = 7.55- 7.60 (m, 3H), 7.23-7.31 (m, 7H), 4.35 (s, 1H), 4.25-4.35 (m, 1H), 4.14 (s, 1H) , 3.81-3.85 (m, 1H), 3.56- 3.63 (m, 6H), 3.38-3.40 (m, 2H), 2.61-2.65 (m, 2H), 1.89-1.92 (m, 2H), 1.52-1.55 ( m, 4H), 1.21-1.31 (m, 2H). 134- 161077.doc 201245190 47 NH Ph Clix Ή-ΝΜΙ^ΟΟΜΗζ, CD3OD): 5(ppm)= 7.57-7.61 (m, 3H), 7.23-7.31 (m, 6H), 4.35 ( s, 1H), 4.28-4.29 (m, 1H), 4.14 (s, 1H), 3.81-3.83 (m, 1H), 3.59-3.64 (m, 6H), 3.40-3.43 (m, 2H), 2.62- 2.65 (m, 2H), 1.89-1.93 (m, 2H), 1.54-1.56 (m, 4H), 1.27-1.32 (m, 2H). 48 NH Ph ό NCxx iH-NMR (400MHz, CDCI3): 6 ( Ppm) = 7.45- 7.55 (m, 5H), 7.31-7.35 (m, 2H), 7.14-7.19 (m, 2H), 4.39 (s, 1H), 4.16-4.21 (m, 1H), 4.08 (s, 1H), 3.89-3.93 (m, 1H), 3.77-3.80 (m, 1H), 3.45-3.59 (m, 4H), 3.29-3.35 (m, 2H), 2.52-2.57 (m, 2H), 1.88- 1.92 (m, 2H), 1.47-1.58 (m, 2H), 1.10-1.19 (m, 2H). 49 NH Ph JH-NMR (400MHz, CD3OD): 5 (ppm) = 7.55-7.62 (m, 3H) , 7.21-7.32 (m, 7H), .4.35 (s, 1H), 4.08-4.19 (s, 2H), 3.82-3.85 (m, 3H), 3.56-3.63 (m, 6H), 3.37-3.46 (m , 4H), 2.60-2.65 (m, 2H), 1.78-1.82 (m, 2H), 1.38-1.48 (m, 2H). 50 NH Ph CI1X iH-NMR (400MHz, CD3OD): 8(ppm) = 7.55 -7.62 (m, 3H), 7.21-7.32 (m, 7H), 4.35 (s, 1H), 4.08-4.19 (s, 2H), 3.82-3.85 (m, 3H), 3.56-3.63 (m, 6H), 3.37-3.46 (m, 4H), 2.60-2.65 (m, 2H), 1.78-1.82 (m, 2H), 1.38-1.48 (m, 2H). 161077.doc •135- 201245190 51 NH Ph Λ NCXX iH-NMR (400MHz, CDCI3): 8 (ppm) = 7.46-7.55 (m, 5H), 7.30-7.35 (m, 2H), 7.15-7.19 (m, 2H), 4.39 (s, 1H), 4.08 (s, 1H), 3.97-4.03 (m, 1H), 3.77-3.80 (m, 3H), 3.29-3.61 (m, 9H), 2.51-2.56 (m, 2H), 1.82-1.85 (m, 2H) , 1.51-1.58 (m, 2H), 1.17-1.27 (m, 2H). 52 NH Ph F (X iH-NMR (400MHz, CD3OD): δ(ρριη) = 7.57-7.60 (m, 3H), 7.23- 7.30 (m, 7H), 4.35 (s, 1H), 4.14 (s, 1H), 4.05-4.07 (m, 1H), 3.82-3.85 (m, 1H), 3.56-3.63 (m, 6H), 3.34- 3.41 (m, 2H), 2.61-2.66 (m, 2H), 1.81-1.96 (m, 6H), 1.47-1.51 (m, 2H). 53 NH Ph F \ c,xx ]H-NMR (400MHz, CD3OD ): 5 (ppm) = 7.69-7.73 (m, 2H), 7.58-7.65 (m, 3H), 7.49-7.54 (m, 2H), 7.26-7.29 (m, 2H), 4.38 (s, 1H), 4.18 (s, 1H), 4.05-4.12 (m, 1H), 3.85-3.90 (m, 1H), 3.72-3.75 (m, 2H), 3.62-3.68 (m, 4H), 3.41-3.44 (m, 2H) ), 2.65-2.68 (m, 2H), 1.90-1.93 (m, 6H), 1.51-1.54 (m, 2H). 136· 161077.doc 201245190

54 NH Ph φ F NCxx 1H-NMR (400MHz, CD3OD): 6(ppm) = 7.69-7.73 (m, 2H), 7.58-7.65 (m, 2H), 7.49-7.54 (m, 2H), 7.26-7.29 (m, 2H), 4.38 (s, 1H), 4.18 (s, 1H), 4.05-4.14 (m, 1H), 3.72-3.75 (m, 2H), 3.62-3.68 (m, 4H), 3.41-3.44 (m, 2H), 2.65-2.68 (m, 2H), 1.78-2.02 (m, 6H), 1.51-1.54 (m, 2H). 55 Ο Ph Λ (X Ή-ΝΜΚ (400ΜΗζ, CD3OD): 6( Ppm) = 7.39-7.46 (m, 3H), 7.15-7.23 (m, 7H), 5.20-5.28 (m, 1H), 4.32 (s, 1H), 4.11 (s, 1H), 3.76-3.79 (m, 1H), 3.48-3.57 (m, 6H), 3.39-3.42 (m, 4H), 3.29-3.34 (m, 2H), 2.58-2.61 (m, 2H), 1.79-1.81 (m, 2H), 1.46- 1.51 (m, 2H). 56 Ο Ph ^OMe II - - « &lt; 1 « «1 rft a ~«····» 瓦 KEK Sfir: S EEEE g^CO 00 —f &lt;-h ^ CO寸^旦旦旦旦旦^&amp; Dandandan § 旦 t 卜 inch (NO&gt;^ Bu: Bu inch K..zhangq Bu of (7) VO VO- CO op op &lt;N ZOo〇v〇rHTtcoin- -^cooom irO^t^VOvOVO^i-ii-HCOCOCOCvI 161077.doc 137- 201245190 57 0 Ph 0l0 Ου iH-NMR (400MHz, CDCI3): 6(ppm) = 7.39-7.47 (m, 3H), 7.14- 7.24 (m, 8H), 6.68-6.70 (m, 1H), 6.52-6.57 (m, 2H), 4.44 (s, 1H), 4.13 (s, 1H), 3.83-3.86 (m, 2H), 3.74-3.77 (m, 1H), 3.44-3.55 (6H, m), 3.26-3.30 (m, 2H), 2.46-2.50 (m, 2H), 1.63-1.70 (m, 2H), 1.37-1.42 (m, 2H), 0.87-0.91 (m, 3H). 58 S Ph Me iH-NMR (400MHz, CD3OD ): 6 (ppm) = 7.50-7.52 (m, 3H), 7.22-7.30 (m, 7H), 4.41 (s, 1H), 4.18 (m, 1Ή), 3.81-3.84 (m, 1H), 3.57- 3.67 (m, 7H), 3.38-3.43 (m, 2H), 2.70-2.72 (m, 2H), 2.40 (d, J = 2.98, 3H). 59 S Ph ό Me〇2C^CX iH-NMR (400MHz , CD3OD): 6 (ppm) = 7.58-7.52 (m, 3H), 7.30-7.21 (m, 6H), 4.42-3.39 (m, 15H), 2.77-2.71 (m, 2H), 2.06-2.00 (m , 2H), 1.73-1.56 (m, 3H), 1.46-1.25 (m, 7H). 60 S Ph ό h〇2CXi^ iH-NMR (400MHz, DMSO-i): 5 (ppm) = 7.57-7.52 ( m, 3H), 7.31-7.28 (m, 2H), 7.21-7.17 (m, 4H), 4.26-3.17 (m, 12H), 2.67- 2.59 (m, 2H), 1.96-1.90 (m, 2H), 1.67- 1.12 (m, 10H). 161077.doc 138- 201245190 61

S

Ph

〇v co2h iH-NMR (400MHz, DMSO-i): 5 (ppm) = 7.56-7.51 (m, 3H), 7.39-7.24 (m, 7H), 4.26-3.20 (m, 9H), 2.64-2.58 ( m, 2H), 1.97-1.89 (m, 2H), 1.63-1.23 (m, 10H). 62

S

Ph

h〇2c〆iH-NMR (400MHz, DMSO-d^): 5 (ppm) = 7.57-7.51 (m, 3H), 7.31-7.21 (m, 6H), 4.50-3.17 (m, 14H), 2.66- 2.58 (m, 2H), 1.98-1.90 (m, 2H), 1.65-1.47 (m, 3H), 1.46-1.25 (m, 7H). 63

S

Ph ό ho2c

^-NMRi^OMHz, DMSO-de): δ(ρρχη)= 7.84-7.81 (m, 2H), 7.56-7.51 (m, 3H), 7.34-7.29 (m, 4H), 4.25-3.16 (m, 9H ), 2.66-2.57 (m, 6H), 1.95-1.93 (m, 2H), 1.68-1.50 (m, 3H), 1.39-1.15 (m, 6H). iH-NMR (400MHz, 64

S

Ph

H02C.

DMSO-de): 7.56-7.52 7.31-7.28 7.184-7.14 4.25-3.27 3.18-3.15 (t, J = Hz, 2H), 2.82-2.75 2H), 2H), 2H), 3H), 6H). 5( Ppm)= (m, 3H) (m, 2H) (m, 4H) (m, 11H) 7.3 (m (m (m (m (m (m (m (m (m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m - 201245190 65 S Ph 零 Ο ~ Ο / iH-NMR (400MHz, CDCI3): 5 (ppm) = 7.50-7.55 (m, 3H), 7.19-7.23 (xn, 3H), 7.12-7.18 (m, 3H) , 4.52 (s, 1H), 4.19 (s, 1H), 4.09-4.15 (m, 2H), 3.86-3.89 (m, 3H), 3.47-3.77 (m, 6H), 3.35-3.38 (m, 1H) , 2.90-2.96 (m, 2H), 2.69-2.72 (m, 2H), 2.57-2.63 (m, 2H), 1.98-2.01 (m, 2H), 1.68-1.17 (m, 2H), 1.58-1.61 ( m, 1H), 1.29-1.44 (m, 4H), 1.18-1.25 (m, 4H). 66 S Ph ό co2h iH-NMR (400MHz, CD3OD): 5 (ppm) = 7.91-7.95 (1H, m) , 7.52-7.56 (3H, m), 7.45-7.50 (3H, m), 7.21-7.27 (2H, m), 4.47 (lH, s), 4.38 (1H, s), 4.19-4.27 (5H, m) , 4.05-4.15 (1H, m), 3.92 (1H, t, J = 5.6 Hz), 3.75-3.84 (1H, m), 3.65 (1H, t, J = 5.6 Hz), 2.74-2.81 (2H, m ), 1.98-2.05 (2H, m), 1.66-1.75 (2H, m), 1.58-1.64 (1H, m), 1.25-1.48 (6H, m). 67 S Ph ό iH-NMR{400MHz, CD3OD) : 5(ppm)= 7.52-7.57 (3H, m), 7.18-7.32 (6H, m), 4.45 (lH, s), 4.23 (1H, s), 3.92-4.05 (6H, m), 3.90 (1H , t, J = 6.0 Hz), 3.75-3.84 (1H, m), 3.65 (1H, t, J = 6.0 Hz), 2.87-2.94 (2H, m), 2.72-2.80 (2H, m), 2.50- 2.58 (2H, m), 1.96-2.03 (2H, m), 1.66-1.75 (2H, m), 1.58-1.64 (1H, m), 1.21-1.48 (6H, m). 161077.doc •140- 201245190 68 S Ph Λ α. H〇2〇vJ iH-NMR (400MHz, CD3OD): 6(ppm) = 7.52-7.57 (3H, m), 7.35-7.41 (3H, m), 7.18-7.27 (3H, m ), 4.47 (lH, s), 4.37 (1H, s), 4.10-4.28 (6H, m), 3.92 (1H, m), 3.79 (1H, m), 3.69 (1H, m), 2.83-2.92 ( 2H, m), 2.69-2.82 (4H, m), 1.96-2.05 (2H, m), 1.66-1.74 (2H, m), 1.55-1.65 (1H, m), 1.21-1.48 (6H, m). 69 S Ph ό Me iH-NMR (400MHz, CD3OD): 6 (ppm) = 7.55-7.54 (m, 3H), 7.27-7.17 (m, 3H), 7.10-7.06 (m, 2H), 4.45 (s, (H, 9H) -2.47 (m, 2H), 2.34-2.33 (m, 3H), 2.03-2.00 (m, 2H), 1.71-1.59 (m, 3H), 1.46-1.22 (m, 5H) 70 S Ph ό Ή-ΝΜΙ (400ΜΗζ, CD3OD): 6 (ppm) = 7.56-7.54 (m, 3H), 7.26-7.19 (m, 3H), 7.15-7.07 (m, 2H), 4.44 (s, 1H), 4.22 (s, 1H), 3.95-3.79 (m, 9H), 3.65 (brt, 1H, J = 5.8 Hz), 2.93-2.88 (m, 2H), 2.79-2.73 (m, 2H), 2.49-2.44 (m, 2H), 2.34-2.33 (m, 3H), 2.02- 2.00 (m, 2H), 1.70-1.59 (m, 3H), 1.46-1.25 (m, 5H) 161077.doc -141 - 201245190 71 S Ph 6 iH-NMR (400MHz, CD3OD): 6(ppm) = 7.54 -7.57 (3H, m), 7.22-7.31 (6H, m), 4.44 (1H, s), 4.22 (lH, s), 3.81-4.02 (10H, m), 3.64 (1H, t, J = 5.6 Hz ), 3.47-3.55 (2H, m), 2.89-2.94 (2H, m), 2.72-2.79 (2H, m), 2.50-2.54 (2H, m), 1.99-2.02 (2H, m), 1.55-1.65 (2H, m). 72 S Ph ό ho2c^ iH-NMR (400MHz, DMSO-d6): 5(ppm) = 7.56-7.50 (m, 3H), 7.31-7.29 (m, 2H), 4.50-3.28 ( m,11H), 2.66-2.50 (m, 2H), 1.98-1.90 (m, 2H), 1.65-1.47 (m, 3H), 1.46-1.25 (m, 6H). 73 S Ph iH-NMR (400MHz, DMSO-&lt;i): 6 (ppm) = 7.56-7.50 (m, 3H), 7.31-7.29 (m, 2H), 4.25-3.38 (m, 7H), 3.17-3.11 (m, 2H), 2.67- 2.59 (m, 2H), 2.37-2.34 (m, 2H), 2.22-2.17 (m, 2H), 1.98-1.90 (m, 2H), 1.65-1.43 (m, 5H), 1.46-1.15 (m, 6H) ). 74 S Ph c1 H-NMR (400MHz, CD3OD): 6 (ppm) = 7.56-7.52 (m, 3H), 7.26-7.22 (m, 2H), 4.45 (s, 1H), 4.23 (s, 1H), 4.19-3.65 (m, 7H), 3.02 (t, J = 7.2 Hz, 2H), 2.77 (dt, J = 18.8 Hz, J = 5.6 Hz, 2H), 2.24-2.17 (m, 2H), 2.06-1.96 (m, 2H), 1.73-1.49 (m, 7H), 1.46-1.30 (m, 8H). • 142· 161077.doc 201245190

75 S

Ph

<RTIgt; m, 2H), 3.88-4.01 (m, 4H), 3.79-3.82 (m, 1H), 3.62-3.68 (m, 1H), 2.94-2.97 (m, 2H), 2.72-2.81 (m, 2H), 2.18-2.22 (m, 2H), 2.00-2.03 (m, 2H), 1.68-1.71 (m, 2H), 1.58-1.60 (m, 3H), 1.47-1.50 (m, 2H), 1.28-1.40 (m 13H). The compounds of Examples 76 to 83 were synthesized according to the method of Example 17 or Example 19. [化85]

ό [Table 3] 161077.doc 143- 201245190 Example No. R3 MS Atlas 76 COOMe M + H+ = 573 77 EtOOC^O^xO^ M + H+ = 631 78 MeOOC, ^^ M + H+ = 601 79 MeOOC^^ M + H+ = 587 80 MeOOC~ M + H+ = 497 81 EtOO(/Vs^ M + H+ = 539 82 EtOOCA^^^ M + H+ = 567 83 XOOEt M + H+ = 609 Example 84: 3-({[ 2-(cyclohexylamino)-4-oxo-3-phenyl-3,5,7,8-tetrahydro&quot;bipyrido[4,3-d]pyrimidin-6(4H)-yl] Manufacture of carbonyl}amino)azetidin-1-carboxylic acid tert-butyl ester

To the compound VII (1 50 mg) was added tetrahydrofuran (8 mL), which was stirred under ice-cooling. Further, diisopropylethylamine (3 12 mg) and three 161077.doc -144·201245190 phosgene (41 mg) were added for stirring for 30 minutes. A solution of (amino)azetidin (103 mg) in tetrahydrofuran (1 mL) was added to the solution, and the mixture was stirred under heating at 50 ° for 7 hours. Water was added to the reaction mixture to quench the reaction to acetic acid. The ethyl ester was extracted. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the residue obtained was purified by an amine propyl column chromatography (hexanes / ethyl acetate = 1 / 1 - ethyl acetate), the compound of Example 84 (90 mg) was obtained. 'H-NMR (400 MHz, CD3OD): δ (ppm) = 7.90 (s, 1H), 7.58-7.62 (m, 3H), 7.26-7.29 (m, 2H), 4.42-4.45 (m, 1H), 4.20 (s, 2H), 4.12-4.16 (m, 2H), 3.89-3.91 (m, 1H), 3.80-3.83 (m, 2H), 3.64-3.68 (m, 2H), 3.29-3.31 (m, 1H ), 2.61-2.64 (m, 1H), 1.81-1.84 (m, 2H), 1.58-1.62 (m, 3H), 1.43 (s, 9H), 1.31-1.34 (m, 2H), 1.09-1.14 (m , 3H). Example 85: 2·(cyclohexylamino)_ν·[1-(4-fluorobenzyl)azetidin-3-yl]-4-oxo-3-phenyl-3,5,7 , the production of 8-tetrahydropyrido[4,3-d]pyrimidine-6(4H)-formamide [Chem. 87]

To the example compound 84 (100 mg), hydrazine (3 mL) was added and stirred under ice-cooling. Further, trifluoroacetic acid (1 mL) was added, and the mixture was stirred at room temperature 161077.doc -145 - 201245190 for 3 hours. After the reaction mixture was concentrated under reduced pressure, diethyl ether (5 mL) was added to the obtained residue, and the precipitated solid was filtered. To the obtained solid, hydrazine, hydrazine dimethylformamide (5 mL) and potassium carbonate (87 mg) were added and stirred at room temperature. A solution of 4_fluorobenzyl bromide (suitable amount) of iN,N-didecylguanamine (1 mL) was added dropwise to stir for 4 hours. Water was added to the reaction mixture to quench the reaction, which was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. After the residue obtained by purifying by a ruthenium column chromatography (decanol/chloroform = 1 / 2 〇), Example Compound 85 (37 mg) was obtained. H-NMR (400 MHz, CD3OD): δ (ppm) = 7.55-7.67 (m, 3H), 7.26-7.33 (m, 4H), 7.01-7.07 (m, 2H), 4.34-4.41 (m, 1H) ), 4.20 (s, 2H), 3.86-3.93 (m, 1H), 3.59-3.68 (m, 6H), 3.07-3.11 (m, 2H), 2.61-2.64 (m, 2H), 1.81-1.89 (m , 2H), 1.55-1.63 (m, 3H), 1.29-1.39 (m, 2H), 1.06-1.19 (m, 3H). Example 86: 6-[(l-Benzylazetidin-2-yl)carbonyl]-2-(cyclohexylamino)-3•phenyl-5,6,7,8-tetrahydropyridine And [4,3-d]pyrimidine-4(3H)-one production [Chemical 88]

Add 1-benzylazetidine-2-carboxylic acid (34 mg), diisopropyl B to a solution of compound VII (54 mg) in N,N-didecylcarbamide (3 mL) Amine (58 mg), 1-hydroxybenzotriazole (34 mg) and 1-ethyl-3-(3-dimethyl 161077.doc • 146· 201245190 aminopropyl) carbodiimide hydrochloride Salt (43 mg). After the reaction mixture was stirred at 25 ° C for 6 hours, a saturated aqueous solution of sodium hydrogencarbonate was added, and ethyl acetate was used for extraction. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by a silica gel column chromatography (hexane / chloroform = 5 / 95) to afford the compound of Example 86 (51 mg). H-NMR (400 MHz, CD3OD): δ (ppm) = 7.55-7.67 (m, 3H), 7.15-7.35 (m, 7H), 4.24-4.36 (m, 1H), 4.09-4.17 (m, 2H ), 3.84-3.93 (m, 2H), 3.74-3.77 (m, 1H), 3.51-3.59 (m, 2H), 3.21-3.25 (m, 1H), 3.01-3.07 (m, 1H), 2.58-2.61 (m, 1H), 2.50-2.53 (m, 1H), 2.21-2.32 (m, 2H), 1.81-1.83 (m, 2H), 1.55-1.62 (m, 3H), 1.32-1.34 (m, 2H) , 1.10-1.15 (m, 3H). Reference Example 4: 2-(cyclohexylamino)_4_oxo_3_phenyl·3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-formic acid Manufacture of tributyl ester [化89]

Step (r4-i): To a pyridine solution (15 mL) of Compound 11 (20 g), EtOAc (16 mL) After the reaction mixture was concentrated under reduced pressure, diethyl ether was added and the precipitated solid was collected by filtration. After washing with diethyl ether and a gas / tetrahydrogen (1:1) solution, compound xVII (17 g) was obtained. Compound IXVII was further purified for use in the next reaction without further 161077.doc -147- 201245190. !H-NMR (300 MHz, DMSO-d6) : δ (ppm) = 1 1.50-1 1.30 (br, 1H), 7.48-7.35 (m, 3H), 7.23-7.18 (m, 2H), 4.02 (s , 2H), 3.56 (t, J = 5.7, 2H), 2.46 (t, J = 5.5, 2H), 1.41 (s, 9H). Step (r4-ii): To a solution of compound XVII (200 mg) in tetrahydrofuran (4 mL) was added Μ-diazabicyclo[5,4,0]-7-undecene (140 μΙ〇, 1 加入) · Benzotriazol-1-yloxy-tris(dimethylamino)hexafluorophosphate scale (387 mg) and mixed. After 4 hours, add cyclohexylamine (1〇〇nL) 'stirring The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen sulfate and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue obtained was purified by ethyl acetate = 1 / 1) to give compound VI (210 mg): 丨H-NMR (400 MHz, CDCI3): δ (ppm) = 7.43-7 52 (m 3H), 7.16-7.22 ( m, 2H), 4.22 (s, 2H), 3.81 (s, 2H), 3 55 (t J=5.8, 2H), 2.54 (s, 2H), 1.97-1.98 (m, 2H), 1.47-1.56 ( m, 3H), 1.41 (s, 9H), 1.25-1.33 (m, 2H), 0.92-1.06 (m, 3H) (consistent with the NMR data of the compound VI of Reference Example 1) Reference Example 5: 2-(4) -Methyl group)-3-phenyl-5,6,7,8·tetrahydron ratio biting and d]pyrimidine-4(3H)·one production [Chemical 90]

161077.doc -148· 201245190 ,J〇

Cbz,

Step (r5-i): To a solution of the compound XVIII (4.67 g) in phenylbenzene (50 mL), EtOAc (2.0 mL) and EtOAc (0.19 g). A reaction solution containing the compound XIX was obtained. After standing to cool, phenyl isocyanate (2.9 mL) was added at 〇 ° C, and stirred at room temperature for 21 hours to obtain a reaction solution containing Compound XX. To the reaction solution, 2 equivalents of hydrochloric acid (9 mL) was added, and after stirring for 22 hours at room temperature, ethyl acetate was added and the insoluble matter was allowed to pass. After the filtrate was extracted with ethyl acetate, the organic layer was washed with water and brine. After drying with anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. After the residue obtained was purified by a silica gel column chromatography (hexane/ethyl acetate), Compound XXI (5.28 g) was obtained. <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The reaction mixture was stirred under heating and reflux for 4 hr and then concentrated under reduced pressure to give Compound XXII ( s. 'H-NMR (400 MHz, CDC13) : δ (ppm) = 7.46-7.29 (m, 10H), 7.10 (t, J=7.4 Hz, 1H), 6.53 (brs, 2H), 5.18 (s, 2H) , 4.26 (s, 2H), 3.64 (t, J = 5.7, 2H), 2.34 (brs, 2H). Step (r5-iii): 161077.doc • 149-201245190 Add 2-(p-tolylhydrazino)acetic acid (126 mg) to a solution of compound XXII (423 mg) in pyridine (3.5 mL) And phosphonium chloride (98 pL). After the reaction mixture was stirred for 5 minutes, it was stirred at room temperature overnight. After adding water, extraction was carried out with ethyl acetate. After washing the organic layer with water and saturated brine, the mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After the residue obtained was purified by a silica gel column chromatography (hexane/ethyl acetate), Compound XXIII (205 mg) was obtained. ^-NMR (400 MHz, CDC13) : δ (ppm) = 7.46-7.44 (m, 2H) 7.31-7.27 (m, 7H), 7.16-7.09 (m, 5H), 6.50 (brs, 1H), 5.17 ( s, 2H), 4.56-4.52 (m, 1H)} 4.42 (dd, J=18.3, 4.2 Hz, 1H), 3.87 (dt, J=2.6, 18.3 Hz, 1H), 3.57 (s, 2H), 3.31 -3.28 (m, 1H), 3.07 (brs, 1H), 2.33 (s, 3H). LC/MS: m/z = 484 (MH+). Steps (r5-iv): To a solution of compound XXIII (133 mg) in diethylbenzene (5 mL), trimethyl hexane (0.52 mL) and triethyl Amine (1.7 mL). After the reaction mixture was stirred at 90 ° C, water was added. After the reaction solution was concentrated, it was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and evaporated. After the residue obtained was purified by a silica gel column chromatography (hexane/ethyl acetate), Compound XXIV (57 mg) was obtained. ^-NMR (400 MHz, CDC13): δ (ppm) = 7.52-7.31 (m, 8H), 6.96 (d, J = 7.9 Hz, 2H), 6.92-6.89 (m, 2H), 6.69 (d, J =7.9 Hz, 2H), 5.18 (s, 2H), 4.45 (s, 2H), 3.81 (t, J=5.8 Hz, 2H), 2.82 (brs, 2H), 2.29 (s, 3H). 161077.doc •150- 201245190 LC/MS : m/z=466 (MH+) Step (r5-v): To a solution of compound XXIV (69 mg) in ethanol (3 mL) % pd-C (64 mg) was stirred under reflux for 6 hours. After filtering with diatomaceous earth, the reaction solution was concentrated. Ammonia water was added and extraction was carried out using gas imitation. The organic layer was washed with brine and dried over anhydrous sodium sulfate. H-NMR (400 MHz, CDC13): δ (ppm) = 7.60-7.35 (m, 3H), 7.00-6.95 (m, 2H), 6.90 (d, J = 8.0 Hz, 2H), 6.69 (d, J =8.〇Hz, 2H), 3.80 (t, J=1.7 Hz, 2H), 3.74 (s, 2H), 3.18 (t, J=5.8

Hz, 2H), 2.75 (tt, J = 5.8, 1.7 Hz, 2H), 2.29 (s, 3H). LC/MS : m/z = 332 (MH+)

Production of pyrimidine-4(3H)-one [Chem. 91]

, Χ) ό Step (r6-i) To a solution of compound XXVI (1.46 to Compound XX. 46 g) in chloroform (6 mL). The reaction mixture was added to a solution of tris-hexane at room temperature. After 5 hours, it was concentrated to give a compound XXVII (335 mg). Triethylamine (4.2 mL) and benzyl chloroformate (0.45 mL) were added to a solution of compound XXVII in tetrahydrofuran (6 mL). The reaction mixture was stirred at room temperature overnight, concentrated under reduced pressure and water. After concentrating the reaction solution, it was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After the residue obtained was purified by a silica gel column chromatography (hexane/ethyl acetate), Compound XXVIII (486 mg) was obtained. ^-NMR (400 MHz, CDC13): δ (ppm) = 9.52 (brs, 1H), 7.52-7.18 (m, 10H), 5.17 (s, 2H), 4.31 (s, 2H), 3.69 (s, 2H) ), 2.37 (brs, 2H). LC/MS: m/z = 332 (MH+): Step (r6- ii): To a solution of compound XXVIII (574 mg) in acetonitrile/N,N-dimethylformamide (3 mL / ΙmL) Iodocyclopentane (0.23 mL) and potassium carbonate (420 mg) were stirred at 11 ° C for 7 hours. After adding water, extraction was carried out with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, and the residue obtained was purified by a gel column chromatography (hexane/ethyl acetate) to obtain a compound hydrazine ( 109 mg). JH-NMR (400 MHz, CDC13) : δ (ppm) = 7.52-7.31 (m, 8H), 7.14-7.11 (m, 2H), 5.43-5.41 (m, 1H), 5.18(s, 2H), 4.41 (s, 2H), 3.77 (t, J = 5.8, 2H), 2.67 (brs, 2H), 1.81-1.76 (m, 2H), 1.66-1.42 (m, 6H). LC/MS: m/z = 446 (MH+). Steps (r6-iii): 161077.doc: 152· 201245190 Compound XXIX (105 mg) was dissolved in ethanol (2. 5 mL). Add 10% Pd/C (50% water) (40 mg). The reaction vessel was internally replaced with hydrogen and stirred at normal temperature and normal pressure for 8 hours. After separating Pd/C by filtration, the filtrate was concentrated under reduced pressure to give Compound XXXI (70 mg). Compound XXXI was not purified for use in the next reaction. * LC/MS : m/z = 312 (MH+). Reference Example 7: l-[4-(3-ethoxy-3-oxopropyl)benzyl]azetidine-3-carboxylic acid trifluoro Production of acetate [Chem. 92]

Et02C,

,C02H (^-i) Et02C

COjH Et〇2C

CHO

XXXI

XXXII

CH3COOH

XXXIII

Co2h CF3COOH Step (r7-i): To a suspension of compound XXXI (3.30 g) in acetonitrile (30 mL), 3-carboxyazetidine (1.65 g), acetic acid (1·4 mL), and Sodium triethoxy borohydride (5.18 g) was stirred at room temperature for a few hours. Water was added to the reaction mixture, and the mixture was concentrated under reduced pressure, and acetonitrile was evaporated. The aqueous layer was washed with hexane/ethyl acetate (1:1). Acetic acid was added to the aqueous layer and extracted with a gas/ethanol (3.1) solution. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. i-NMR (300 MHz, DMS〇-d6) : δ (ppm) = 7 66 (d, J = 8 6, 2H), 7.62 (d, J = 16.7, 1 Η), 7·32 (d, J = 8山2H),6 59 (4) 1.90 J-16.0, 1H), 4.17 (q, J=7.1, 2H), 3.60-3.10 (m, 7H), (s,3H), 1.24 (t, J = 7.1, 3H). 161077.doc -153- 201245190 Step (r7-ii): To a solution of compound XXXII (3.29 g) in tetrahydrofuran / ethanol / acetic acid (1 : i : 1) (50 mL), 5% Pt / C (50% water) (658 mg), stirred at room temperature for 2 hours under an air atmosphere. The reaction mixture was subjected to celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol (33 mL), and difluoro-acetic acid ( 837 μί) was added and concentrated under reduced pressure. After adding water and washing the aqueous layer with a hexane/ethyl acetate (1:1) solution, the target was extracted from the aqueous layer by gas/ethanol (3: hydrazine). After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure. After dissolving the residue in a hexane/ethyl acetate (丨:2) solution, the target product was precipitated, and hexane was further added and stirred for 30 minutes. The precipitated solid was collected by filtration and dried to give a compound as a white solid (2.49 g): H-NMR (300 MHZ, DMSO-d6) ·· δ (ppm) = 7 34 (4) j=8 2H), 7.27 (d, J = 8.3, 2H), 4.24 (s, 2H), 4.13-3.97 (m, 4.02 (q, J=7.2, 2H), 3.61-3.47 (m, 1H), 2.85 (t , J = 7.5, 2H) 2.60 (t, J=7.5, 2H), 1.13 (t, J=7.2, 3H) 〇' Example 87 Κ4·[(3_Π2_(cyclopentyloxy)_4•oxo winter benzene The base w &amp; tetrahydrobite and [4,3-d] bite _6 (4 Η) · base] ruthenium azacyclobutane ·! 'methyl phenyl} phenyl} ethyl propionate manufacturing [化93]

161077.doc 87 154· 201245190 To a solution of compound XXX (34 mg) in N,N-didecylguanamine (1 mL), Compound XXXIII (49 mg), triethylamine (0.02 mL) Benzotriazole (16 mg) and 1-ethyl-3-(3-didecylaminopropyl)carbodiimide hydrochloride (25 mg) were stirred at room temperature overnight. Then, a saturated sodium hydrogencarbonate solution was added to the reaction solution, and extraction was carried out using ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the obtained residue was purified by a column chromatography (methanol/methanol) and then purified by reverse phase preparative HPLC (water/acetonitrile) to obtain Example Compound 87 (13) Mg). ^-NMR (400 MHz, CDC13): δ (ppm) = 7.45-7.40 (m, 3H), 7.22-7.08 (m, 6H), 5.42-5.35 (m, 1H), 4.45 (s, 0.6H), 4.14 (s, 1.4H), 4.11-4.08 (m, 2H), 3.84 (t, 1=5.92 Hz, 2H), 3.64-3-52 (m5 5H), 3.43 (t, J=7.10 Hz, 1H) , 3.34 (t, J=7.12 Hz, 1H), 2.90 (m, 2H), 2.64-2.55 (m, 4H), 1.77-1.74 (m, 2H), 1.60-1.57 (m, 2H), 1.48-1.41 (m, 4H), 1.22-1.18 (m, 3H). LC/MS: m/z = 585 (MH+) </ RTI> </ RTI> The compound of the above Example 65 can be synthesized from the compound IX of the above-mentioned Example 17 by the same procedure as in Reference Example 7 and this. Reference Example 8: Production of 1,1-difluoro-3-isothiocyanate-cyclobutane [Chem. 94]

HCI f c F

rfF H2N scn^

XXXIV XXXV To a solution of compound XXXIV (298 mg) in chloroform (4 mL) was added 161077.doc: 155-201245190 about (5 19 mg) in water (4 mL) and immersed in an ice bath. After adding thiophosgene (0.16 mL) dropwise, the mixture was warmed to room temperature and stirred for 4 hours. To the reaction liquid, water was added, and the mixture was extracted twice with a gas-purified mixture, and the organic layer was combined and dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford compound ν (219 mg). Compound XXXV was not purified for use in the next reaction. 'H-NMR (400 MHz, CDC13): δ (ppm) = 4.18-4.08 (m, 1H), 3.13-2.99 (m, 2H), 2.91-2.76 (m, 2H). Examples 88 to 200: In Examples 88 to 96, a compound synthesized according to Reference Example 1 or Reference Example 4 and a compound synthesized according to Reference Example 7 were used, and the synthesis was carried out by the method according to Example 87. In Examples 97 to 124, the synthesis was carried out in accordance with Example 17 or Example 19. In Examples 125 to 153, the compound synthesized according to Reference Example 7 and the compound synthesized according to the method for producing Compound IX of Example 7 were synthesized by the method of Example 87. In Examples 154 to 160, the compound synthesized according to the production method of the compound XXV of Reference Example 5 and the compound synthesized according to Reference Example 7 were synthesized by the method according to Example 87. In Example 161, the compound synthesized according to Reference Example 7 and Compound XXX were used, and the synthesis was carried out according to the method of Example 87. In Examples 162 to 200, the corresponding ester compounds described in the examples were used, and the synthesis was carried out by the method according to Example 2A. Further, in the production of the compounds of the above respective examples, the corresponding isothiocyanate was used instead of the phenyl isothiocyanate in the step (Π) of Reference Example 1. The isothiocyanate is commercially available or can be produced by the method of Reference Example 8 using 161077.doc-156-201245190 or according to the method. [化95] 0 0

[Table 4] Example No. X Ri R2 R3 Ή-NMR spectrum or MS spectrum 88 NH ό Me〇2CXu Ή-NMR (300 MHz, CDCla): 5 (ppm) = 7. 62-7.45 (m, 3H), 7 .25-7.16 (m, 6H), 4.45 (s, 0.6H), 4.1 4 (s, 1.4H), 4.00-3. 81 (m, 3H), 3.69 ( s, 1H), 3.68 (s, 2H ), 3.65-3.48 (m, 7 H), 3.40-3.29 (m, 2H), 2.65-2.52 (m, 2H), 1.92-1.80 (m , 2H), 1.62-1.49 ( m, 3H), 1.43- 1.21 (m, 2H), 1.20-0.92 (m, 3H). 89 NH ό Me02C-Q^ Ή-NMR (400MHz, CDCU): δίρριη)53 7. 29-7.18 (m, 4H), 6.79- 6.68 (m, 1H), 4.51- 4.19 (m, 1.6H), 4.19-4.08 (m, 2. 4H), 4.08-3.91 (m, 1H), 3.91-3.71 (m , 5H), 3.71-3.52 ( m, 9H), 3.52-3.27 (m, 3H), 2.52 (t, J = 6.0Hz, 2H), 2.2 0-2.05 (m, 1H), 2. 05-1.83 (m, 4H), 1.83 -1.51 (m, 3H), 1.51- 1.33 (m, 2H), 1.33-1.08 (m, 4H) 161077.doc -157- 201245190 90 Ο _2〇〇^ Ή-NMR (400ΜΗζ, CDCI3): 6 (ppm ) = 7. 52-7.48 (m, 2Η), 7. . . . . . . . . . . . . . . . . . . . . . . (s , 1.6H), 3.79 (t, 1. 6H, J = 5.8 Hz), 3.69 (s, 0.6H), 3.68 (s, 2.4H), 3.63-3.4 6 (m, 7.4H), 3.30 ( t, 2H, J = 6.7 Hz), 2.64 (t, 2H, J = 5 .7 Hz). 91 Ο ό Me02C-Q^ iH-NMR (400MHz, CDCI3): δ(ρρχη)= 7. 57-7.45 (m, 3H ), 7 .38-7.29 (m, 4H), 7.25-7.22 (m, 5H), 7.07-7.05 (m, 2H), 4.51 (s, 0.6H), 4. 19 (s, 1.4H), 3.82 (t, 1.4H, J = 5.9 H z), 3.68 (s, 3H), 3. 60-3.48 (m, 7.6H), 3.33 (dd, 2H, J = 12.1, 5.6 Hz), 2.5 5-2.49 (m, 2H). 92 Ο _2〇〇^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 53-7.47 (m, 3H), 7. 31-7.29 (m, 2H), 7.27- 7.22 (m, 5H), 6.80-6.77 (m, 1H), 6.68-6.63 (m, 1H), 6.61-6.60 (m, 1 H), 4.51 (s, 0.6H), 4.19 (s, 1.4H) , 3.8 2 (t, 1.4H, J = 5.9 Hz), 3.78 (s, 3H), 3.68 (s, 3H), 3.61-3.50 (m, 7.6H), 3. 35-3.16 (m, 2H), 2 .57-2.51 (m, 2H). 161077.doc 158- 201245190 93 0 /0 Μβ入Μβ Me〇2C^XX. iH-NMR (400MHz, CDCI3): δ(ρρχη)= 7. 54-7.44 ( m, 3H), 7 .31-7.28 (m, 2H), 7.25-7.19 (xn, 5H), 6.76-6.72 (m, 1H), 6.63-6.58 (m, 2H), 4.52-4.46 (m, 1 6H), 4.19 (s, 1.4H), 3.82 (t, 1.4H, J = 5.9 Hz), 3.68 (s, 3H), 3.60-3.49 (m , 7.6H), 3.36-3.30 (m, 2H) , 2.57-2.53 (m, 2H), 1.31 (d, 6H, J = 6.1 Hz). 94 Ο JO ά. MeO^ Me〇2C-0^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 54-7.46 (m, 3H), 7.30-7.22 (m, ?H), 6.80-6.78 (m , 1H), 6.67-6.63 (m, 2H), 4.51 (s, 0.6H), 4. 19 (s, 1.4H), 4.08 (t, 2H, J = 4.7 Hz), 3.82 (t, 1.4H, J = 5.8 Hz), 3.74-3.7 1 (m, 2H), 3.68 (s, 3H), 3.61-3.50 (m , 7.6H), 3.43 (s, 3 H), 3.36-3.30 (m, 2H), 2.56-2.52 (m, 2H). 95 Ο JO ά.乂Ή-NMR (400MHz, CDCI3): 5 (ppm) = 7. 58-7.43 (m, 4H), 7.40-7.18 (m, 6H), 6.76 (d, J = 8.0Hz, 1H), 6.69 -6.55 ( m, 2H), 4.51 (s, 0. 8H), 4.19 (s, 1.2H), 3.91 (t, J = 6.4H z, 2H), 3.82 (t, J = 5.7Hz, 1H), 3.80-3.28 (m, 13H), 2.5 6 (t, J = 5.6Hz, 2 H), 1.80-1.68 (m, 2H), 1.53-1.40 (m, 2H), 0.96 (t, J = 7.3Hz, 3H). 161077.doc -159- 201245190 96 S 0 Me02C-Q^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 61-7.56 (m, 3H), 7 •46-7.33 (m, 7H), 7.22-7.21 (m, 4H), 4.49 (s, 0.6H), 4. 17 (s, 1.4H), 3.77 (t, 1.4H, J = 5.9 H z), 3.69 (s, 0.9H ), 3.68 (s, 2.1H), 3.6 0-3.49 (m, 7H), 3. 45 (t, 0.6H, J = 5. 9 Hz), 3.33-3.29 ( m, 2H) ( 2.55-2.49 ( m, 2H). 97 S ό Ή-NMR (300MHz, CDCI3): 5 (ppm) = 7. 58-7.45 (m, 3H), 7.25-7.08 (m, 3H), 7.00- 6.90 (m, 2H), 4.51 (s, 0.6H), 4. 19 (s, 1.4H), 4.19-4.08 (m, 2H), 3.92 -3.83 (m, 1H), 3.8 1-3.65 (m, 1H), 3 65-3.48 (m, 6H), 3 .40-3.29 (m, 2H), 3.00- 2.87 (m, 2H), 2.75-2.65 (m, 2H), 2.65-2.55 (m, 2H), 2.05- 1.90 (m, 2 H), 1.75-1.50 (m, 2H), 1.50-1.30 (m, 4H), 1.30-1. 2 (m , 5H). 98 S ό 】H-NMR (300MHz, CDCI3): 5 (ppm) = 7. 58-7.49 (m, 3H), 7.30-7.08 (m, 6H), 4.51 (s , 0.5H), 4.2 1 (s, 1.5H), 4.28-4. 09 (m, 2H), 3.92-3 .83 (m, 1H), 3.83-3.67 (m, 1H), 3.70 -3.45 (m , 6H), 3.3 5-3.22 (m, 2H), 2. 80-2.52 (m, 6H), 2 .10-1.90 (m, 2H), 1.80-1.50 (m, 2H), 1.50-1.30 (m , 4H) , 1.30-1.15 (m, 5H )· 161077.doc -160- 201245190 99 S ό Ή-NMR (300MHz, CDCls): δ(ρριη)= 7. 56-7.48 (m, 3H), 7 . 31-7.17 (m, 6H), 4.51 (s, 0.6H), 4.1 9 (s, 1.4H), 3.92-3. 83 (m, 1H), 3.83-3 .65 (m, 1H), 3.63- 3.45 (m, 9H), 3.40 - 3.29 (m, 2H), 2.7 5-2.60 (m, 2H), 2. 05-1.95 (m, 2H), 1.75-1.60 (m, 2H), 1.60- 1.52 (m, 1H), 1.50-1.30 (m, 4H), 1.30-1.13 (m, 3H), 1.05-0.95 (m, 2 H). 100 S /O ό Ή-NMR (300MHz, CDCla): 5 (ppm) = 7. 56-7.45 (m, 3H), 7.25-7.15 (m, 4H), 6.88-6.80 (m, 2H), 4.63-4.57 (m, 2H), 4.51 (s, 0.7H) ), 4. 33-4.20 (m, 2H), 4 .19 (s, 1.3H), 3.92-3.83 (in, 1H), 3.83 -3.65 (m, 1H), 3.6 3-3.45 (m, 6H) , 3. 40-3.22 (m, 2H), 2 .75-2.60 (m, 2H), 2.10-1.90 (m, 2H), 1.80-1.50 (m , 2H) , 1.50-1.33 (m, 4H ), 1.30-1.15 (m, 5 H). 161077.doc 161 · 201245190 101 S ό Ή-NMR (300MHz, CDCI3): 5(ppm) = 7. 56- 7.45 (m, 3H), 7 •25-7.16 (m, 3H), 6.95-6.75 (m, 3H), 4.65-4.58 (m, 2H), 4.51 (s, 0.6H), 4. 33-4.20 ( m, 2H), 4 .20 (s, 1.4H), 3.92-3.83 (m, 1H), 3.83 -3.65 (m, 1H), 3.6 3-3.45 (m, 6H), 3. 40-3.28 (m , 2H), 2 .75-2.60 (m, 2H), 2.10-1.90 (m, 2H), 1.80-1.50 (m, 2H), 1.50-1.33 (m, 4H ), 1.30-1.15 (m, 5 H 102 S JO ό Μβ〇2〇/Ν^ίι Ή-NMR (300MHz, CDCI3): 5(ppm)= 7. 56-7.48 (m, 3H), 7.25-7.10 (m, 4H), 6.90-6.74 (m, 2H), 4.51 (s, 0.6H), 4. 21 (s, 1.4H), 4.00-3.90 (m, 2H), 3.92 -3.83 (m, 1H), 3.8 3-3.65 ( m, 6H), 3. 63-3.50 (m, 4H), 3 .48-3.39 (m, 2H), 2.88-2.80 (m, 2H), 2.75-2.63 (m, 2H) , 2.05-1.95 (m , 2H ), 1.75-1.60 (m, 2 H), 1.50-1.30 (m, 4H), 1.30-1.13 (m, 2H). 162- 161077.doc 201245190 103 S ό Ή-NMR (300MHz, CDCI3): 5(ppm)= 7. 99-7.94 (m, 1H), 7.62-7.48 (m, 4H), 7.24-7.19 (m, 2H), 6.87-6.79 (m, 1H), 4.92-4.87 (m , 2H ), 4.51 (s, 0.6H), 4.19 (s, 1.4H), 3. 92-3.83 (m, 1H), 3.82 -3.70 (m, 4H), 3.6 3-3.48 (m, 6H), 3. 40-3.28 (m, 2H), 2.75-2.65 (m, 2H), 2.05-1.93 (m, 2H), 1.75-1.60 (m, 2H), 1.50-1.30 (m, 4H), 1.30-1.13 (m, 2 H). 104 S ό Me02C Ή-NMR (300MHz, CDCI3): 5 (ppm) = 7. 58-7.35 (m, 5H), 7.25-7.15 (m, 2H), 4.95-4.60 (m, 3H), 4.51 (s, 0.6H), 4. 20 (s, 1.4H), 3.92-3.83 (m, 1H), 3.82 -3.70 (m, 4H), 3.6 3-3.48 (m, 5H), 3. 40-3.25 (m, 2H), 2 .78-2.65 (m , 2H), 2.08-1.93 (m, 2H), 1.75-1.60 (m, 2H), 1.50-1.30 (m, 4H), 1.30-1.13 (m, 2 HI 105 S ό Ή-NMR (300MHz, CDCI3) : 5(ppm)= 7. 58-7.35 (m, 3H), 7.25-7.15 (m, 2H), 4.51 (s, 0.7H), 4.2 1 (s, 1.3H), 3.92-3. 83 (m, 1H), 3.82-3 .70 (m, 1H), 3.70-3.48 (m, 6H), 3.30 -3.19 (m, 2H), 2.7 8-2.65 (m, 2H), 2. 45-2.35 (m, 2H), 2 .34-2.23 (m, 2H), 2.08-1.93 (m, 2H), 1.75-1.50 (m, 6H), 1.50-1.15 (m, 9H ) -163- 161077.doc 201245190 106 S ό iH-NMR (300ΜΗζ, CDCI3): 5 (ppm) = 7. 58-7.45 (m, 3Η), 7.25-7.18 (m, 2H), 4.51 (s, 0.6H), 4.2 1 ( s, 1.4H), 4.10-4. 05 (m, 2H), 3.92-3 .83 (m, 1H), 3.82-3.70 (m, 4H), 3.68 -3.43 (m, 5H), 3.3 2-3.20 (m, 2H), 2. 78-2.65 (m, 2H), 2.59-2.45 (m, 2H), 2.09-1.93 (m, 2H), 1.75-1.50 (m, 6H), 1.50-1.15 (m, 5H)· 107 S ό Ή-NMR (400MHz, CDCI3): 5 (ppm) = 7. 21-7.15 (m, 4H ), 4 .86-4.71 (m, 1H), 4.46 (s, 0.6H), 4.1 4 (s, 1.4H), 3.91-3. 74 (m, 3H), 3.69 ( s, 3H), 3.61 ( s, 2H ), 3.62-3.48 (m, 5 H), 3.39-3.27 (m, 4H), 2.92-2.78 (m, 2H), 2.60 (t, J = 5.8Hz, 2H), 2.12-2. 03 (m, 2H), 1.82-1 .71 (m, 2H), 1.70-1.30 (m, 6H). 108 S /N, JO ό ί^[ Ή-NMR (300MHz, CDCI3): 5(ppm)= 8. 73 (d, J = 4.8H, 1 H), 8.46 (s, 1H), 7. 57 (d, J = 8.2Hz, 1H), 7.53-7.42 (m, 1H), 7.32-7.11 (m , 4H), 4.60-4.44 (m, 0.7H), 4.18 (s, l. 3H), 3.95-3.48 (m, 13H), 3.45-3.27 (m, 2H), 2.70 (t, J = 5.9Hz, 2H), 2. 15-1.90 (m, 2H), 1.75-1.55 (m, 2H), 1.47-1.15 (m, 6H). -164- 161077.doc 201245190 109 S ό iH-NMR (300MHz, CDCla): 5 (ppm) = 8.67 (d, J = 4.9 Hz, 1H), 7.90 (t, J = 7.9 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1H), 7. 31 (d, J = 7.7Hz, 1H), 7.28-7.10 (m, 4H), 4.49 (s, 0.6H), 4.17 (s, 1.4H), 3.90-3.45 (m, 13H), 3.40-3.27 (m, 2H), 2.66 (t, J = 5.9H z, 2H), 2.08-1.92 (m, 2H), 1.78-1.50 ( m, 4H), 1.49-1.15 (m, 4H). 110 s ό Ή-NMR (300MHz, CDCI3): 5 (ppm) = 7. 29-7.10 (m, 4H), 4.49-4.28 (m, 1H), 4.14 (s, 0.6H), 4.1 0-3.97 (m, 1.4H), 3.96-3.69 (m, 5H), 3.66 (s, 3H), 3.64 -3.44 (m, 8H), 3.4 0- 3.25 (m, 2H), 2. 59 (t, J = 5.5Hz, 2 H), 2.18-1.82 (m, 5H), 1.82-1.55 (m, 3H), 1.55-1.12 (m , 6H). 111 s π ό Me02C^Ok/ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 36-7.23 (m, 7H), 7.22-7.14 (m, 2H), 5.27-7.20 (m, 2H ), 4.51 (s, 0.7H), 4. 19 (s, 1.3H), 3.92-3.80 (m, 3H), 3.71 -3.67 (in, 3H), 3.6 7-3.46 (m, 7H), 2. 67-2.59 (m, 2H), 2 .64 (t, J = 6.0Hz, 2H), 2.10-1.97 (m, 2H), 1.80-1.67 (m , 2H), 1.66-1.52 ( m, 2H), 1.52-1.37 (m, 4H), 1.37-1.31 (m, 1H). -165- 161077.doc 201245190 112 S ό MeOzC^Ok/ Ή-NMR (400MHz, CDCla): 5(ppm)= 7. 30- 7.10 (m, 4H), 4.45 (s, 0.7H), 4.19-4.08 (m, 3.3H), 3. 89-3.77 (m, 3H), 3 .72-3.65 (m, 7H), 3.64 -3.45 (m, 7H), 3.44-3.27 (m, 2H), 2.68-2.48 (m, 8H ), 2.11-1 .98 (m, 2 H), 1.81-1.68 (m, 2H), 1.68-1.21 (m, 6H). 113 S π ό Ή-NMR (400MHz, CDCI3): 6 (ppm) = 8. 53 (d , J = 6.1Hz, 2H), 7.32-7.11 (m, 6H), 5.27-5.17 (m , 2H), 4.50 (s, 0.8 H), 4.18 (s, 1.2H), 3.91-3.79 (m, 3H ), 3.70-3.65 (m, 4H), 3.65-3.47 (m, 6H), 3.45- 3.27 (m, 2 H), 2.65 (t, J = 5. 8, 2H), 2.17-1.93 (m, 2H) ), 1.77-1.65 (m, 2H), 1.65-1.20 (m, 6H). 114 SF Lf ό UL/ Ή-NMR (300MHz, CDCI3): 5 (ppm) = 7. 25-6.95 (m, 2H) , 6. . . . . . . . . . . . . . . . . . . . 12 (s, 1.3H), 3.95-3.72 (m, 5H), 3.72 -3.44 (m, 5H), 3.4 4-3.24 (m, 2H), 2. 95-2.70 (m, 2H), 2.58 (t, J = 5.5 Hz, 2H), 2.11-1.93 (m, 2H), 1.78-1.67 (m, 2H), 1.67-1.18 (m, 6H), 1.28 (t, J = 7.1 Hz, 3H). 166· 161077.doc 201245190 115 S j〇rMe ό XX/ iH-NMR (400MHz, CDCI3): δ(ρρπχ)= 8. 33 (d, J = 2.5Hz, 1H), 7.43 (dd, J = 8.3Hz , 2.5Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.27-7.12 (m, 2H), 6.90-6.7 9 (m, 2H), 4.63-4. 38 (m, 2.9H), 4.24 (q, J = 7.0Hz, 2H ), 4.17 (s, 1.1H) , 4 .05-3.25 (m, 10H), 2.69 (t, J = 5.7Hz , 2H), 2.63 (s, 3H), 2.06-1.90 (m, 2H) , 1.90 - 1.51 (m, 2H ), 1.47 -1.18 (m, 6 H), 1.27 (t, J = 7. OHz, 3H). Λ Ή-NMR (400MHz, CDCI3): 5 (ppm) = 8. 57 (d, J = 5.0Hz, 1H) , 8.29 (s, 1H), 7.29 (d, J = 5.0Hz, 1H), 7.28-7.16 ( m, 2H), 6.90-6.79 (m, 2H), 4.72-4.35 (m, 3H), 4.24 (q , 116 S &quot;V Me XX/ J = 7.1Hz, 2H), 4. 19 (s, 1H), 3.94-3. 25 (in, 10H), 2.71 (t, J = 5.8Hz, 2H), 2.13 (s, 3H), 2.05 -1.72 (m, 2H), 1.7 2-1.52 (m, 2H), 1. 46-1.18 (m, 6H), 1.27 (t, J = 7.1Hz, 3H). 161077.doc 167- 201245190 117 S ό Ή-NMR (400MHz, CDCla): 6(ppm)= 7. 30-7.17 (m, 2H), 6.94-6.79 (m, 2H), 4.77-4.58 (m , 2H), 4.58-4.32 (m, 1.8 H), 4.26 (q, J = 7. 1Hz, 2H), 4.16 (s, l. 2H), 4.16-4.00 ( m, 2H), 3.99-3.68 (m , 5H), 3.68-3.43 (m, 5H), 3.43-3.2 7 (m, 2H), 2.61 (t, J = 5.9Hz, 2H), 2.17-1.83 (m, 5H), 1.83-1.38 ( m, 8H), 1.38- 1.25 (m, 4 H). 118 S ό Ή-NMR (400MHz, DMSO-de): 5 (ppm) = 7.54-7.52 (m, 3H), 7.32-7.24 (m, 3H) j, 7.16-7.12 (m, 3 H), 4.26 (s, 1.3H), 4.08 (s, 0.7H), 3.7 5-3.44 (πχ, 11H), 3 .40-3.32 (m, 2H), 3.18 (t, J = 7.28 Hz, 2H), 2.67-2.59 (m, 2H), 1.96-1.9 2 (m, 2H), 1.60-1. 50 (m, 3H), 1.35-1 .28 (m, 4H), 1.23- 1.19 (m, 1H). 119 S ό Ή-NMR (400MHz, DMSO-de): 5 (ppm) = 7.54-7.52 (m, 3H), 7.33-7.31 (m, 2H), 7.26-7.24 (m, 1 H), 7.16-7.12 (m, 3H), 4.27 (s , 1.3H) , 4.09 (s, 0.7H), 3. 85-3.81 (m, 1H), 3.76-3.72 (m, 1H), 3.66-3.44 (m, 9H), 3.40-3.32 (m, 2H) , 3.19 (t, J = 7.32 Hz, 2H), 2.64-2.6 3 (m, 2H), 2.10-2. 09 (m, 2H), 1.57-1 .53 (m, 4H), 1.46-1.41 (m, 2H). 161077.doc -168 - 201245190 120 s ό EtOaC^O^^v XX/ iH-NMR (400MHz, CDCI3): 6(ppm)= 7. 46-7.43 (m, 3H), 7 .16-7.11 (m, 4H), 6.78 (t, J = 9.16 Hz, 2H), 4.54 (s, 1 H), 4.52 (s, 1H), 4. 44 (s, 0.6H), 4.22-4.17 (m, 2H), 4.13 (s, 1.4H), 3.86-3.7 9 (m, 2H), 3.57-3. 46 (m, 4H), 3.34-3 .28 (m, 2H), 2.65-2.62 ( m, 2H), 2.10 -2.04 (in, 2H), 1.6 5-1.40 (m, 8H), 1. 25-1.20 (m, 3H). 121 s ό 0 MeA0^/ iH-NMR (400MHz, CDCI3) : 6(ppm)= 7. 52-7.49 (m, 3H), 7. 22-7.19 (m, 2H), 4.49 (s, 0.6H), 4.1 9 (s, 1.4H), 4.07-4. 02 (m, 2H), 3.86 (t, J = 5.84 Hz, 2 H), 3.75-3.64 (m, 3H), 3.57 -3.53 (m, 2H), 3.38-3.32 (m , 2H), 2.71-2.66 ( m, 4H), 2.06 (s, 1 H), 2.04 (s, 1H), 1. 99-1.97 (br, 2H) ), 1.69-1.66 (br, 3H), 1.41-1.33 (m, 4H), 1.23-1.19 (m, 1H) 161077.doc 169· 201245190 122 S ό 0 Me Human iH-NMR (400MHz, CDCI3) : 6(ppm)= 7. 55-7.51 (m, 3H), 7.24-7.21 (m, 2H), 4.51 (s, 0.6H), 4.2 1 (s, 1.4H), 4.08-4. 02 (m, 2H), 3.88 (t , J = 5.92 Hz, 2H), 3.78-3.74 (m, 1H ), 3.63-3.49 (m, 4 H), 3.29-3.23 (m, 2H), 2.72 (t, J = 5 .68 Hz, 2H), 2.48-2.41 (m, 2H), 2.05 (s, 1H), 2.03 (s, 2 H), 2.01-1.98 (m, 2H), 1.71-1.59 (m, 5H ), 1.45-1.32 (m ,6H). 123 s ό Me02Cv^^. Uk/ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 94-7.89 (m, 2H), 7.46-7.43 (m, 3H), 7.33-7.27 (m, 2H), 7.15-7.12 (m, 2H), 4.45 (s, 0.7H), 4. 13 (s, 1.3H), 3.84-3.79 (m, 5H) , 3.72 -3.48 (m, 7H), 3.3 9-3.29 (m, 2H), 2. 66-2.60 (m, 2H), 1.94-1.91 (m, 2H), 1.64-1.51 (m, 3H) , 1.35-1.24 (m, 3H) 170- 161077.doc 201245190 124 S ό Et0zC^( X. Ή-NMR (400MHz, DMSO-de): 6 (ppm) = 7.56-7.51 (m, 3H), 7.31-7.28 (m, 2H), 7.18-7.08 (m, 4 H), 4.25 (s, 1.2H), 4.07-4.01 (m, 2.8H), 3.73-3.52 (m, 4 H), 3.48-3.42 (m, 3H), 3.37-3.30 (m, 2H), 3.17 (t, 2H, J = 7.2 Hz), 2.63-2.50 (m, 4H), 2.29 -2.23 (m, 2H), 1.9 8-1.89 (m, 2H), 1. 85-1.75 (m, 2H), 1.65-1.47 (m , 3H), 1.39-1.29 (m, 4H), 1.18-1.14 (m, 3H) 125 S 乂ό Μ3〇2ο-〇^ Ή-NMR (300MHz, CDCU): 5(ppm)= 7. 40-7.15 (m, 4H), 4.84-4.69 (m, 1H), 4.44 (s, 0.6H), 4.1 2 (s, 1.4H), 3.95-3. 72 (m, 5H), 3.72-3 .44 (m, 5H), 3.66 ( s, 3H), 3.59 (s, 2H ), 3.44 - 3.24 (m, 2 H), 2.95-2.74 (m, 2H), 2.58 (t, J = 5 .1Hz, 2H ), 2.11-1.9 5 (m, 2H), 1.92-1. 67 (m, 2H), 1.67-1 .18 (m, 6H). 126 S Xi ό —XL/ Ή-NMR (400MHz, CDCla): 5 (ppm) = 7. 32-7.14 (m, 4H), 4.46 (s, 0.8H), 4.13 (s, 1.2H), 3.99-3.8 3 (m, 5H), 3.80 (t, J = 6.0 Hz, 2H), 3.74-3.40 (m, 12H), 3.38-3.25 (m, 2H), 2.61 (t, J = 6.0 Hz, 2H), 2.20-1.97 (m, 3H), 1.82-1.6 9 ( m, 2H), 1.69-1. 20 (m, 10H). 171 · 161077.doc 201245190 127 S XT ό Μ 〇20^〇^ iH-NMR (400MHz, CDCI3): 5(ppm)= 8.33 (d, J = 2.5Hz, 1H), 7.43 (dd, J = 8.3Hz, 2.5Hz, 1H), 7.29 ( d, J = 8.3 Hz, 1H), 7.27-7.16 (m, 4H), 4.63-4.3 7 (m, 1H), 4.17 (s, 1H), 3.95-3.25 (m , 15H), 2.70 (t, J =6.0Hz, 2H), 2.63 (s, 3H), 2.07-1.88 (m, 2H), 1.74-1.6 2 (m, 2H), 1.47-1. 30 (m, 4H), 1.40-1 .15 ( m, 2H). 128 S Me ό _2c-Q^ Ή-NMR (400MHz, CDCI3): 6(ppm)= 8. 57 (d, J = 5.0Hz, 1H), 8.29 (s, 1H), 7.29 ( d, J = 5.0 Hz, 1H), 7.28-7.14 (m, 4H), 4.68-4.35 (m, 0.9H), 4.18 (s, 1.1H), 3.95-3.47 (m, 13H), 3.47-3.28 ( m, 2H), 2.71 (t, J = 5.8Hz, 2H), 2. 12 (s, 3H), 2.04-1. 90 (m, 2H), 1.72-1 .62 (m, 2H), 1.45- 1.28 (m, 4H), 1.28 -1.15 (m, 2H). 129 S ό Me02C-Q^ Ή-NMR (400MHz, CDCI3): 6 (ppm) = 7. 36-7.17 (m, 4H), 4 . 58-4.32 (m, 1.9H), 4.16 (s, 1.1H), 4. 14-3.97 (m, 2H), 3.97-3.69 (m, 5H), 3.69-3.65 (m, 3H), 3.65 -3.43 (m, 7H) , 3.43 - 3.23 (m, 2H ), 2.62 (t, J = 6.1 Hz, 2H), 2.13-1.82 (m, 5H), 1.81-1.6 7 (m, 3H), 1.67- 1. 23 (m, 6H). 161077.doc 172· 201245190 130 S ό Ή-NMR (400MHz, CD CI3): 5 (ppm) = 8. 74 (dd, J = 4.8 Hz, 1.6 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 7.59 (td, J = 8.1 Hz, 1.6 Hz, 1H ), 7. 51-7.39 (m, 1H), 7.33-7.18 (m, 4H), 4.64-4.52 (m, 0.9H), 4.19 (s, 1.1H), 3.97-3.30 (m, 15H), 2.72 (t, J = 6.0Hz, 2H), 2.07-1.90 ( m, 2H), 1.78-1.49 (m, 2H), 1.49-1.32 (m, 4H), 1.32-1.1 8 (m, 2H 131 S ό Me〇2C-0^ Ή-NMR (400MHz, CDCI3): 6(ppm)= 7. 30-7.13 (m, 4H), 4 .57-4.31 (m, 1H), 4.16 (s , 1H), 4.15-3.88 (m, 4H), 3.88 -3.47 (m, 13H), 3. 47- 3.37 (m, 2H), 2.61 (t, J = 5.8Hz, 2H), 2.30-2.11 (m , 2H), 2.10-1.82 (m, 3H), 1.82-1.40 (m, 7H). 132 S ό Me〇2c-Q^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 8. 65 (dd , J = 4.8Hz, 1.5Hz, 1H), 8.48 ( dd, J = 7.9Hz, 1.5 Hz, 1H), 7.35-7.20 (m, 5H), 4.64-4.4 2 (m, 0.9H), 4.20 ( s , 1.1H), 4.03-3.72 (m, 3H), 3.72-3.4 8 (m, 10H), 3.48-3 .30 (m, 2H), 2.72 ( t, J = 5.9Hz, 2H), 2.36 (s , 3H), 2.07-1.92 (m, 2H), 1.77 -1.49 (m, 2H), 1.4 9-1.31 (m, 4H), 1. 31-1.18 (m, 2H). 173- 161077.doc 201245190 133 S ό iH-NMR (400MHz, CDCI3): 5 (ppm) = 8. 56 (s, 1H), 8.29 (s, 1H), 7.40 (s, 1H), 7.33-7.18 (m, 4H), 4.63-4.36 (m, 0.9 H), 4.19 (s, 1.1H), 3.97-3.29 (m, 15H), 2.72 (t, J = 6.0H z, 2H), 2.42 (s, 3H ), 2.07-1.85 (m, 2 H), 1.76-1.48 (m, 2H), 1.48- 1.31 (m, 4H), 1.31-1.18 (m , 2H). 134 S OMe ό Me〇2CXu iH-NMR (400MHz, CDCI3): 5(ppm) = 7. 33 (d, J = 8.7Hz, 2H) , 7.30-7.17 (m, 4H), 6.83 (d, J = 8.7Hz, 2H), 5.21-5. 11 (m, 2H), 4.50 ( s, 0.7H), 4.18 (s, 1 .3H), 4.06-3.94 (m, 1H), 3.82 (t, J = 5.8Hz, 2H), 3.78 (s , 3H), 3.75-3.47 ( m, 10H), 3.47-3.28 (m, 2H), 2.62 (t, J = 5.8 Hz, 2H), 2. 27-2.12 (m, 2H), 1.81-1.43 (m, 6H). 135 S ό Me〇2C-Q^ Ή-NMR (400MHz, CDCI3): 5( Ppm) = 7. 36-7.17 (m, 4H), 4. 58-4.32 (m, 1.9H), 4.16 (s, 1.1H), 4. 14-3.97 (m, 3H), 3.97-3.28 (m, 16H), 2.62 (t, J = 6.1Hz, 2H), 2.13-1.82 (m, 5H), 1.81-1.67 (m, 3H), 1.67-1.23 (m, 6H). 161077.doc 174- 201245190 136 S OMe ό Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 33 (d, J = 8.7Hz, 2H), 7.28-7.15 (m, 4H), 6.81 (d, J = 8.7Hz , 2H), 5.20-5. 11 (m, 2H), 4.50 ( s, 0.7H), 4.1 6 (s, 1 .3H), 3.91-3.71 (m, 6H), 3.66 (s, 3H), 3.63-3.43 (m, 7H), 3.42-3.27 (m, 2H ), 2.60 (t, J = 5.8 Hz, 2H), 2.10-1.97 (m, 2H), 1.80-1.6 7 (m, 2H), 1.67-1. 20 (m, 6H). 137 S ό Me〇2C-Q^ Ή-NMR (400MHz, (CD, 3H), 7. 3 .97-3.28 (m, 16H), 2.62 (t, J = 6.1Hz , 2H), 2.13-1.82 ( m, 5H), 1.81-1.67 (m, 3H), 1.67-1.23 (m, 6H). 138 S Cl ό Me〇2CXu Ή-NMR (400MHz, CDCI3): 5(ppm) = 7. 57 (dd, J = 7.9Hz, 1.5Hz, 1H), 7.51-7.38 (m, 2H), 7.32 -7.18 (m, 5H), 4.6 8-4.40 (m, 0.8H), 4.21 (s, 1.2H), 4.0 2-3.90 (m, 1H), 3. 88-3.73 (m, 2H), 3.73- 3.48 (m, 10H), 3.47-3.27 (m, 2H), 2.72 (t, J = 5.8H z, 2H), 2.09-1.94 ( m, 2H), 1.79-1.48 (m, 2H), 1.48-1.3 1 (m, 4H), 1.41-1. 19 (m, 2H). 161077.doc 175- 201245190 139 S 1 ό _2〇q^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 38- 7.18 (m, 5H), 6.43-6.37 (m, 2Pi), 6.34-6.29 (m, 1H), 5.28-5.20 (m, 1H), 4.68-4.40 (m, 1.1 H), 4.18 (s, 0.9H), 3.96-3.84 (m, 1H), 3.81 (t, J = 5.8Hz, 2H), 3.78- 3.32 ( m, 12H), 2.62 (t, J = 5.8Hz, 2H), 2.1 4-2.02 (m, 2H), 1. 83-1.70 (m, 2H), 1.70-1.21 (m, 6H) 140 S ό Me〇zCXu Ή-NMR (400MHz, CDCI3): 6(ppm) = 7. 33-7.18 (m, 4H), 4.90-4.37 (m, 1.9H), 4.31-4.10 (m, 2.1 H), 3.97-3.58 (m, 14H), 3.58-3.45 (m , 2H), 3.40-3.33 ( m, 4H), 2.69-2.59 (m, 2H), 2.15-2.02 (m, 2H), 1.84 -1.7 0 (m, 2H), 1.70-1. 23 (m, 6H). 141 S ό Me〇2C^Q^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 38-7.13 (m , 9H), 4 .51 (s, 0.9H), 4.28-4.13 (m, 3.1H), 3. 96-3.84 (m, 1H), 3.83 (t, J = 5.9Hz, 2H), 3.71 -3.30 (m, 12H), 3.07-2.88 (m, 2H), 2.64 (t, J = 5.8Hz, 2H), 2.15 -2.02 (m, 2H), 1.8 5-1.72 (m, 2H), 1. 72-1.23 (m, 6H). 176· 161077.doc 201245190 142 S Me ό iH-NMR (400MHz, CDCI3): 5 (ppm) = 7. 45-7.05 (m, 8H), 4. 71-4.38 ( m, 0.9H), 4.20 (s, 1.1H), 4. 00-3.30 (m, 15H), 2.72 (t, J = 6.0Hz, 2H), 2.18-2.07 (m , 3H), 2.06-1.93 ( m, 2H), 1.75-1.62 (m, 2H), 1.47-1.29 (m, 4H), 1.29-1.1 8 (m, 2H). 143 S OMe ό Me02C-Q^ Ή-NMR (400MHz, CDCI3): 5 (ppm) = 7. 52-7.45 (m, 1H), 7 .31-6.99 ( In, 7H), 4.61-4.44 (m, 0.9H), 4.20 (s, 1.1H), 4 .00-3.30 (m, 18H), 2.71 (t, J = 5.8Hz, 2H), 2.06-1.93 ( m, 2H), 1.77-1.62 (m, 2H), 1.47-1.29 (m, 4H), 1.29-1.1 7 (m, 2H). 144 S .N. OMe ό Me〇2C-Q^ Ή-NMR ( 400MHz, CDCI3): 5(ppm)= 8. 61 (d, J = 5.7Hz, 1H), 8.26 (s, 1H), 7.33-7.15 (m, 4H), 6.98 (d, J = 5.7H z, 1H), 4.71-4.38 (m, 0.9H), 4.20 (s, l. 1H), 3.98-3.83 (m, 3H), 3.83-3.65 (m, 7H), 3.65-3.58 (m, 6H), 3.58 -3.3 0 (m, 2H), 2.71 (t, J = 5.9Hz, 2H), 2 .09-2.02 (m, 2H), 1.73-1.48 (m, 2H), 1.48-1.31 (m, 4H) , 1.31-1.18 (m, 2H )· 177· 161077.doc 201245190 145 S ό Ή-NMR (400MHz, CDCI3): 5(ppm) = 7. 33-7.18 (m, 4H), 4.65-4.40 (m , 0.9H), 4.16 (s, 1.1H), 4. 16-4.03 (m, 2H), 3.97-3.82 (m, 1H), 3.82 (t, J = 6.0Hz, 2H), 3.73-3.66 (m , 5H), 3.66-3.55 ( m, 4H), 3.55-3.41 (m, 4H), 3.39-3.31 (m, 4H), 2.62 (t, J = 6.0Hz, 2H), 2. 14-2.02 (m, 2H), 2 .02-1.91 (m, 2H), 1.84- 1.70 (m, 2H) , 1.70-1.38 (m, 4H j, 1.38-1.24 (m, 2 HI. 146 S ό Me〇zCXu Ή-NMR (400MHz, CDCI3): 5 (ppm) = 7. 42-7.15 (m, 4H), 4 .90-4.32 (m, 2H), 4.16 (s, 1H), 4.16-3.72 (m, 9H), 3.72 - 3.68 (m, 5H), 3.6 8-3.56 (m, 4H), 3 56-3.44 (m, 2H), 2 .90-2.59 (m, 3H), 2.16-1.94 (m, 3H), 1.87-1.70 (m, 3H), 1.70-1.39 (m, 4H ), 1.39- 1.15 (m, 2 HI. 147 S Λ Me〇2CXu Ή-NMR (400MHz, CDCI3): 5(ppm) = 7. 25-7.16 (m, 4H), 6.10-5.88 (m, 1H), 4.73 -4.64 (m, 2H), 4.49 (s, 0.8H), 4. 17 (s, 1.2H), 3.95-3.78 (m, 2H), 3.71 -3.67 (m, 3H), 3.6 4-3.47 (m , 8H), 3. 40-3.28 (m, 2H), 2 .87-2.79 (m, 3H), 2.64 (t, J = 6.1Hz, 2H), 2.13-1.98 (m , 2H), 1.82- 1.70 ( m, 2H), 1.70-1.24 (m, 6H). 161077.doc •178· 201245190 148 S 0 ό Me〇2CXu Ή-NMR (400MHz, CDCla): 5(ppm)= 7. 25-7.15 (m , 4H), 6. 20-5.91 (m, 1H), 4.70-4.63 (m, 2H), 4.49 (s, 0.8H), 4. 17 (s, 1.2H), 4.08-3.95 (m, 1H) , 3.83 (t, J = 5.8 Hz, 1H), 3.72-3.66 (m, 3H), 3.65-3.46 (m, 8 H), 3.39-3.28 (m, 2H), 2.86-2.78 (m, 3H), 2.65 (t, J = 6.0 Hz, 2H), 2.28-2. 11 (m, 2H), 1.82-1.46 (m, 6H). 149 S ό iH-NMR (400MHz, CDCI3): 5(ppm) = 7 23-7.09 (m, 4H), 4. 58-4.32 (m, 1.8H), 4.15 (s, 1.2H), 4. 11 (q, J = 7.2Hz, 2H), 4.07-3.69 (m, 6H), 3.64-3.44 (m , 6H), 3.39-3.26 ( m, 2H), 2.92 (t, J =7.6Hz, 2H), 2.69 -2.45 (m, 4H), 2.1 2-1.83 (m, 5H), 1. 83-1.58 (m, 3H), 1. 58-1.19 (m, 9H). 150 S Me ό Me〇2CXu iH-NMR {300MHz, CDCI3): 5(ppm)= 7. 34-7.16 (in, 4H), 4. 52-4.42 (m, 1H), 4.20-3.92 (m, 3H), 3.92-3.73 (m, 4H), 3.73-3.42 (m, 10 H), 3.42-3.24 (m, 5H), 2.63 (t, J = 6. 4Hz, 2H), 2.15-1.9 5 (m, 2H) , 1.83-1. 70 (m, 2H), 1.70-1 .24 (m, 6H), 1.24-1.13 (m, 3H). 161077.doc 179· 201245190 151 S ό Ή-NMR (400MHz, DMSO-d6 ): δ(ρρχη)= 7.54-7.52 (m, 3H) , 7.33-7.31 (m, 2H ), 7.21-7.19 (m, 4 H), 4.27 (s, 1.3H), 4.09 (s, 0.7H) , 3.8 5-3.82 (m, 1H), 3. 74 (t, J = 5.60 Hz, 1H), 3.65-3.44 (m , 7H), 3.39-3.19 ( m, 4H), 3.19 (t, J = 7.28 Hz, 2H), 2. 66-2.61 (m, 2H), 2 .12-2.08 (m, 2H), 1.59-1.41 (m, 6H). 152 S ό Et02C\x^s^s. Ή-NMR (400MHz, CDCI3): 5 (ppm) = 7. 53-7.52 (m, 3H), 7.24-7.13 (m, 6H), 4.52 (s, 0.6H), 4.2 0 (s, 1.4H), 4.16-4. 10 (m, 2H), 3.94-3.87 (m, 2H), 3.61 -3.54 (m, 5H) , 3.3 9-3.32 (m, 2H), 2. 95-2.90 (m, 2H), 2.73-2.70 (m, 2H), 2.62-2.58 (m, 2H), 2.18-2.13 (m, 2H) , 1.89 (br, 1H), 1. 66-1.58 (m, 4H), 1.53-1.48 (m, 2H), 1.26-1.22 (m, 3H). 153 S Me02C-Q^ Ή-NMR (400MHz , DMSO-de): 6 (ppm) = 7.56-7.53 (m, 3H), 7.34-7.30 (m, 2H), 7.23-7.20 (m, 4 H), 4.26 (s, 1.3H), 4.19-4.12 (m, 1H) , 4.08 (s, 0.7H), 3. 74 (t, 1H, J = 5.6 4 Hz), 3.65-3.44 ( m, 9H), 3.37 (t, J = 7.20 Hz, 1H), 3. 18 (t, J = 7.28 Hz, 2H), 2.61-2.60 (m, 2H), 2.39-2.36 (m, 2H), 1.98-1.91 (m, 4H), 1.36 (s, 1H). - 161077.doc 201245190 154 ch2 ό Me〇2CXu 1H-NMR (400MHz, CDCI3): 5(ppm) = 7.45-7.54 (m, 3H), 7.15-7.24 (m, 4H), 6.90-6.97 (m , 2H) , 4.26 (s, 1H), 4.0 5 (s, 1H), 3.72-3.8 2 (m, 2H), 3.43-3. 58 (m, 6H), 3.24-3 .31 (m, 2H) , 2.51-2.56 (m, 2H), 1.70 -1.73 (m, 2H), 1.4 4-1.52 (m, 3H), 1. 18-1.24 (m, 2H), 0 .97-1.04 (m, 3H) 155 ch2 φ Me Me02C-Q^ Ή-NMR (400MHz, CDCI3): 5(ppm) = 7. 47-7.37 (m, 3H), 7.23-7.19 (m, 4H), 6.97 (d, 2H , J = 7 .9 Hz), 6.92-6.90 ( m, 2H), 6.70-6.67 (m, 2H), 4.53 (s, 0.66), 4.20 (s, 1.4H), 3.90 (t, 1.4H, J = 5.9 Hz), 3.74 (s, 1.4H), 3.73 (s, 0.66), 3.69-3.67 (m, 3H), 3.64-3.49 (m , 7.6H), 3.39-3.32 (m, 2H), 2.81-2.76 (m, 2H), 2.28 (s, 3H). 156 ch2 ά0Μβ Me〇zCXu Ή-NMR (400MHz, CDCI3): 5 (ppm) = 7. 43-7.39 (m, 3H), 7.23-7.21 (m, 4H), 7.10-7.06 (m, 1H), 6.91 (d, 2H , J = 6.8 Hz), 6.74-6.72 (m, 1H), 6.39-6.35 (m, 2H), 4.53 (s, 0.7H), 4.21 (s, 1.3 H), 3.91 (t, 1.3H, J = 5.9 Hz), 3.77 ( s, 1.3H), 3.75 (s, 0 .7H), 3.70-3.67 (m, 6H), 3.61-3.52 (m , 7.7H), 3.37-3.32 (m, 2H), 2.81 -2.77 (m, 2H). 161077.doc -181- 201245190 157 CH Me Φ Cl Me02c^(x iH-NMR (400MHz, CDCI3): 5(ppm)= 7. 57-7.51 (m, 1H), 7 .48-7.41 (m, 1H), 7.32-7.19 (m, 6H), 7.15 (d, 2H, J = 8.4 Hz), 6.81 (d, 1 H, J = 8.4 Hz), 6. 78 (d, 1H, J = 8.1 Hz), 6.53 (d, 1H, J = 8.1 Hz), 4.53 ( s, 0.6H), 4.21 (s, 1 .4H), 3.96-3.87 (m, 1.4H), 3.75 (q , 1 H, J = 7.0 Hz), 3. 69-3.67 (m, 3H), 3 .62-3.53 (m, 7.6H), 3.37-3.32 (m, 2H), 2.81-2.79 (m, 2H ) , 1.47 (t, J = 7.0 Hz, 3H). 158 CH Me ό Me〇2〇Q^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 57-7.51 (m, 1H), 7.48-7.41 (m, 1H), 7.24-7.16 (m, 9H) , 6.86-6.82 (m, 2H), 6.49-6.47 m, 1H), 4.53 (s, 0.7H), 4. 20 (s, 1.3H), 3.96-3.87 (m, 1.3H), 3. 76 ( q, 1H, J = 6.9 Hz), 3.69-3.67 (m, 3H), 3.61-3.55 (m , 7.7H), 3.39-3.32 (m, 2H), 2.88-2.81 (m, 2H), 1.50 (t , J = 6.9 Hz, 3H). 161077.doc 182· 201245190 159 CH2 F ό Me〇2C^XX/ Ή-NMR (400MHz, CDCla): 6(ppm)= 7. 54-7.48 (m, 1H), 7.33-7.18 (m, 7H), 4.61-4.45 (m, 0.6H), 4.21 (s, 1.4H), 3.96 (dt, 0.7H, J = 13.4, 7.3 Hz), 3.83 (dt, 0.7H, J = 13. 4, 7.3 Hz), 3.69-3. 68 (m, 3H), 3.61-3.55 (m, 7.6H), 3.3 9-3.32 (m, 2H), 2. 75- 2.71 (m, 2H), 2 .40-2.33 (m, 2H), 2.23-2.16 (m, 1H), 1.70-1.65 (m, 4H), 1.57-1.44 (m, 4H )· 160 ch2 F ό Me0zCXu Ή-NMR (400MHz, CDCI3): 5 (ppm) = 7. 53-7.48 (m, 1H), 7.33-7.18 (m, 7H), 4.59 (d, 0.3H, J = 18.7 Hz), 4.48 (d, 0.3H, J = 18.7 H z), 4.21 (s, 1.4H), 3.94 (dt, 0.7H, J = 13.3, 5.7 Hz), 3.8 4 (dt, 0.7H, J = 1 3.3, 5.7 Hz), 3.69-3.68 (m, 3H), 3.63 -3.52 (m, 7.6H), 3. 39-3.30 (m, 2H), 2.76-2.71 (m, 2H), 2.33-2.19 (m, 2H), 1.75-1.55 (m, 5H), 1.25-1.01 (m, 4H), 0.84 -0.75 (m, 2 H). 183· 161077.doc 201245190 161 0 ό Me〇2C^Q^ Ή-NMR (400MHz, CDCI3): 5(ppm)= 7. 41-7.36 (m, 3H), 7 .17-7.14 (m, 4H), 7.07-7.04 (m, 2H), 5.37-5.34 (m, 1H), 4.41 (s, 0.6H), 4. 10 (s, 1.4H), 3.80 (t, J = 5.88 Hz, 2 H), 3.62-3.61 (m, 3H), 3.54-3.45 (m, 7H), 3.33-3.26 (m , 2H), 2.59-2.55 ( m, 2H), 1.75-1.70 (m , 2H), 1.58-1.53 (m, 2H), 1.46-1.3 7 (m, 4H). 162 S ό Ή-NMR (400MHz, DMSO-de): 6 (ppm) = 7.56-7.54 (m, 3H) , 7.40-7.37 (m, 3H ), 7.33 - 7.28 (m, 3 H), 4.31 (s, 3H), 4. 03-4.00 (m, 6H), 3.78 (t, J = 5.64 Hz , 1H ), 3.70-3.67 (m, 1H), 3.60 (d, J = 5.00 Hz, 2H), 3.55 (t, J = 5.52 Hz, 1H), 2.69-2.55 (m, 2H), 1.99-1.92 ( m, 2H), 1.61-1.51 (m, 3H), 1.38-1.3 1 (m, 4H), 1.23-1. 21 (m, 1H). 163 S ό h〇2C^XX/ Ή-NMR (400MHz, DMSO-d6): 5 (ppm) = 7.55-7.53 (m, 3H), 7.33-7.22 (m, 6H), 4.28 (s, 1H), 4.1 0 (s, 1H), 3.87-3.8 2 (m, 2H), 3.77-3. 74 (m, 7H), 3.55-3 .47 (m, 3H), 2 .67-2.62 (m, 2H), 2.12 -2.09 (m, 2H), 1.6 0-1.51 (m, 4H), 1. 48-1.43 (m, 2H). 184· 161077.doc 201245190 164 S ό H02C \^5s. ,XX/ Ή-NMR (400MHz, CDCI3): 5(ppm)= 8. 06-8.01 (m, 2H), 7.53-7.44 (m, 5H), 7.22-7.21 (m, 2H ), 4.54 (s, 1H), 4.26 (s, 1H), 4.16 (t, J = 8.08 Hz, 1H), 4 .09-4.01 (m, 2H), 3.97 (s, 1H), 3.91 (t, J = 6.04 Hz, 2 H), 3.84-3.62 (m, 5H), 2.01-1.99 (m, 2H), 1.69 (br, 3H) , 1.43-1.32 (m, 4H )· 165 S ό Χλ/ M + H+ = 575 166 s ό H02C^(XM + H+ = 573 167 sh〇2C^Oz M + H+ = 545 168 s ό H〇2C^0^ M + H+ = 605 169 s /0 ό _j〇^ M + H+ = 587 170 s ό ho2c, ^o, ^^ XX/ M + H+ = 589 171 s ό ho2c^o_n M + H+ = 590 -185- 161077.doc 201245190 172 S Lf ό h〇2c^jCl^ M + H+ = 587 173 S JO ό M + H+ = 574 174 S JO ό H〇2Cv^JOx^ M + H+ = 574 175 S ό M + H+ = 581 176 S ό H〇2C&gt;^0^ M + H+ = 587 177 SF ό M + H+ = 587 178 S / F r~^F ό Η0^°Π/ M + H+ = 603 179 S ό h〇2CXL/ M + H+ = 595 180 S XT ό h〇2C^Oz M + H+ = 588 -186- 161077.doc 20 1245190 181 S Me ό H02cxk/ M + H+ = 588 182 S ό υυ M + H+ = 604 183 S Me ό M + H+ = 604 184 S /N, JO ό h〇2C^XX. M + H+ = 574 185 S 〇 η〇2〇ΎΧ^ M + H+ = 581 186 S ό h〇2CXi^ M + H+ = 567 187 S ό h〇2C^0^ M + H+ = 588 188 S ό ό h〇2C^(X/ M + H+ = 588 189 S 1 ό h〇2C^XX. M + H+ = 577 -187- 161077.doc 201245190 190 S ό η〇2〇Χ^ M + H+ = 555 191 S ό H〇2c-Q^ M + H+ = 581 192 S ό H〇2C^0^ M + H+ = 595 193 S 丫〇, Me Me ό η〇2°0/ M + H+ = 569 194 ch2 JO ό H〇2c-Q^ M + H+ = 555 195 ch2 φ Me M + H+ = 563 196 ch2 JO ά0Μθ h〇2CXl. M + H+ = 579 197 o M + H+ = 565 161077.doc -188 - 201245190 198 0 ό h〇2C^Oz 551 199 S j 〇ό M + H+ = 559 200 S ό H〇2C^XX M + H+ = 601 Example 201: 2·(cyclohexylsulfanyl)-6-{[l-(2-hydroxyethyl)azacyclocycle Ding Xuanji] Manufacture of carbonyl}-3-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one [Chem. 96]

To a solution of the title compound 121 (23 mg) in THF (0.5 mL) / EtOAc. After the reaction mixture was stirred at room temperature for 3 hours, it was concentrated under reduced pressure, and then was evaporated. The mixture was extracted with a gas mixture, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, it was filtered and concentrated under reduced pressure to give Example 2 (1 mg). !H-NMR (400 MHz, CDC13) : δ (ppm) = 7.53-7.50 (m, 3H), 7.23-7.20 (m, 2H), 4.51 (s, 0.6H), 4.21 (s, 1.4H), 3.88 (t, J=5.88 Hz, 2H), 3.74-3.39 (m, 9H), 2.72-2.61 (m, 4H), 2.17 161077.doc -189· 201245190 (s, 1H), 2.01-1.99 (br, 2H), 1.71-1.58 (m, 3H), 1.43-1.34 (m, 4H). Example 202: 2-(cyclohexylsulfanyl)-6-{[l-(4-hydroxybutyl)azetidin-3-yl-yl]yl}-3-phenyl-5,6 ,7,8-tetrahydro^»ιfc bite and [4,3-d] bite-4(3H)-ketone manufacture [Chemical 97]

Using Example Compound 122, Example Compound 202 (68 mg) was obtained according to Example 201. ^-NMR (400 MHz, CDC13): δ (ppm) = 7.54-7.51 (m, 3H), 7.23-7.20 (m, 2H), 4.51 (s, 0.7H), 4.20 (s, 1.3H), 3.87 (t, J=5.88 Hz, 1H), 3.79-3.64 (m, 4H), 3.61-3.53 (m, 4H), 3.35-3.29 (m, 2H), 2.73-2.71 (m5 2H), 2.54-2.48 ( m, 2H), 2.01-1.99 (m, 2H), 1.69-1.35 (m, 11H) » Example 203: 3-{4-[(3-{丨2-(cyclohexylsulfanyl)-4- Oxo-3-phenyl-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidin-1-yl)methyl Manufacture of 2-phenylethyl propionate 2-methoxyethyl ester [Chem. 98]

161077.doc -190- 201245190 To a solution of the compound of Example 64 (50 mg) in N,N-didecylamine (2 mL) was added 2-methoxyethanol (65 mg) three. Sit (17 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (25 mg). After the reaction mixture was stirred at room temperature for 20 hours, a saturated aqueous sodium hydrogencarbonate solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained residue was purified by EtOAc (EtOAc/EtOAc) (EtOAc). H-NMR (300 MHz, CDC13): δ (ppm) = 7.58-7.45 (m, 3H), 7.25-7.08 (m, 6H), 4.51 (s, 0.6H), 4.28-4.16 (m, 3.4H) , 3.92-3.83 (m, 1H), 3.82-3.65 (m, 1H), 3.65-3.48 (m, 8H), 3.43-3.28 (m, 5H), 3.00-2.87 (m, 2H), 2.75-2.60 ( m, 4H), 2.05-1.92 (m, 2H), 1.80-1.50 (m, 3H), 1.50-1.12 (m, 5H). Examples 204-206: According to the method of Example 203, the compounds of Examples 2〇4 to 2〇6 were synthesized from the corresponding tickic acid and ethylene glycol, diamine or the atmosphere described in the present Example. [化99]

[Table 5] 16J077.doc -191 - 201245190 Example No. R3 Ή-NMR spectrum or MS spectrum 204 M + H+ = 631 205 Ή-NMR (300 MHz, CDCI3): 6 (ppm) = 7.58-7.48 (m, 3H) ), 7.25-7.12 (m, 3H), 7.02-6. 90 (m, 2H), 4.51 (s, 0.6H), 4.19 (s, 1.4H), 3.92-3.83 (m, 1H), 3.82-3.67 (m, 1H), 3 .66-3.48 (m, 6H), 3.43-3.28 (m, 2H), 3.0 0-2.87 (m, 8H), 2.75-2.65 (m, 2H), 2.64-2.53 (m , 2H), 2.05-1.92 (m, 2H), 1.75-1. 50 (m, 3H), 1.50-1.12 (m, 5H). 206 Ή-NMR (300MHz, CDCI3): 6(ppm) = 7.58- 7.48 (m, 3H), 7.25-7.10 (m, 3H), 7.02-6. 90 (m, 2H), 5.45-5.25 (m, 2H), 4.51 (s, 0 .6H), 4.19 (s, 1.4 H), 3.92-3.83 (m, 1H), 3 .82-3.67 (m, 1H), 3.66-3.48 (m, 6H), 3.4 3-3.28 (m, 2H), 3.03-2.90 (m, 2H) , 2.75-2.65 (m, 2H), 2.57-2.45 (m, 2H), 2.05-1. 92 (m, 2H), 1.75-1.50 (m, 3H), 1.50-1.12 (m, 5H). Reference example 9 : Production of methyl (3-aminophenyl)acetate [100] o2n&quot;C^c〇2H' (r9-i) C02Me

H2N C02Me

XXXVI

XXXVII

XXXVIII Step (r9-i): To a solution of Compound XXXVI (1.00 g) in DMF (5.00 g), EtOAc. Water was added to the reaction liquid, and extraction was carried out with acetic acid. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by a silica gel column chromatography (hexane/ethyl acetate) to afford Compound XXXVII (1.00 g). 'H-NMR (300 MHz, CDC13) : δ (ppm) = 8.15 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.50 (t , J=7.5 161077.doc -192- 201245190

Hz, 1H), 3.73 (s, 2H), 3.71 (s, 3H). Step (r9-ii): To a solution of the compound XXXVn (l. 〇〇 g) in a solution (5.00 g), 1% Pd/C (200 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 4.5 hours. The reaction solution was filtered with celite, and concentrated under reduced pressure, whereby compound XXXVIII (832 mg) was obtained in a yield of 98%. It was used in the next step without purification. !H-NMR (300 MHz, CDC13) : δ (ppm) = 7.09 (t, J = 7.5 Hz 1H), 6.53-6.50 (m, 3H), 3.67 (s, 3H), 3.52 (s, 2H) ). Example 207: (3-{6[(l-Benzylazetidin-3-yl)carbonyl) 2(cyclohexylthioalkyl)-4-oxo-5,6,7,8 - Manufacture of tetrahydrogen 0 Λ and 丨 4,3-d] mouth bite-3 (4H)-yl}phenyl)acetate methyl ester [Chem. 101]

Using the compound χχχνιιι obtained in Reference Example 9, the compound of Example 207 was obtained by the method of Reference Example 1, Reference Example 2, and then Example 17. 'H-NMR (300 MHz, CDC13) : δ (ppm) = 7.51-7.35 (m, 2H), 7.35-7.20 (m, 5H), 7.20-7.05 (m, 2H), 4.48 (s, 0.9H) , 4.17 (s, 1.1H), 3.83 (t, J=5.7 Hz, 2H), 3.80-3.15 (m, 13H), 2.68 (t, J=5.7 Hz, 2H), 2.05-1.95 (m, 2H) , 1.75-1.48 (m, 2H), 1.48-1.12 (m, 6H). 161077.doc 193- 201245190 Reference Example 10: Preparation of ethyl 3-(4-mercaptophenyl)propionate [Chem. 96]

XXXIX Add 4,3-diethoxyprop-1-ene (8.44 g), triethylamine (6.03 1111 〇, IV) to a solution of 4-bromobenzaldehyde (XXXIX, 4.00 g) in DMF (21.6 mL) Butyl ammonium hydride (6.01 §) and palladium acetate (11) (146 11^) were stirred and heated under stirring for 12 hours at 90 ° C. The reaction solution was cooled to room temperature, and water (86.4 mL) was added to acetic acid The ester was subjected to extraction, and the obtained organic layer was washed successively with 0.2% hydrochloric acid and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. /1) Purification of the obtained residue to give the title compound ( XXXX, 3.13 g) 0 'H-NMR (300 MHz, CDC13): δ (ppm) = 9.98 (s, 1H), 7.81 (d, J = 8.2 Hz , 2H), 7.37 (d, J=8.2 Hz, 2H), 4.12 (q, J=7.1 Hz, 2H), 3.03 (t, J=7.7 Hz, 2H), 2.66 (t5 J=7.7 Hz, 2H) 1.23 (t, J = 7.1 Hz, 3H). LC/MS: m/z = 207 (MH+) Further, the compound XXXX can be used in the synthesis of a compound such as the above Examples 65, 149, 152, etc. 208 : 3-{4-[(3-{[2-(cyclohexylsulfanyl)-4)oxo-3-phenyl-3,5,7,8-tetrahydropyrido[4,3-d Pyrimidine Manufacture of ethyl pyridine-6(4H)-yl]sulfonyl}azetidin-1-yl)methyl]phenyl}propionate 161077.doc •194· 201245190 [化102] (ex208-i ) (ex208.ii)

CF3COOH (ex208-iii) Step (ex208-i) Compound IX (75 mg) was dissolved in N,N-didecylguanamine (2 mL), and triethylamine (0.07 mL) was added dropwise with ice-cooling. ). Then, 3-tert-sulfonyl-azetidin-1-butyric acid tert-butyl ester (77 mg) was added, and the mixture was allowed to stand overnight at room temperature. A saturated sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The residue obtained was purified by a silica gel column chromatography (hexane/ethyl acetate) to afford compound (1). H-NMR (400 MHz, CDC13): δ (ppm) = 7.53-7.49 (m, 3H), 7.21-7.20 (m, 2H), 4.25-4.22 (m, 4H), 4.17-4.08 (ra, 2H) , 4.03-3.97 (m5 1H), 3.74-3.71 (m, 1H), 3.66-3.64 (m, 2H), 2.80-2.77 (m, 2H), 2.03 (s, 1H), 1.99-1.97 (m, 2H) ), 1.70- 1.67 (m, 2H), 1.43 (s, 9H), 1.40-1.33 (m, 3H), 1.24 (t, J=7.20 Hz, 2H) ° LC/MS : m/z=561 (MH+ In the step (4) (4)), the compound χχχχπ is obtained according to the method of Reference Example 3. Following the procedure of the compound XXXX obtained in the step (βχ208_π〇, 匕 161077.doc • 195-201245190 and Reference Example 10), the compound of Example 208 (5 1 mg) was synthesized according to the method of Example 19. H-NMR (400 MHz, DMSO-d6): δ (ppm) = 7.54-7.51 (m, 3H), 7.31-7.29 (m, 2H), 7.16 (S, 4H), 4.34 (m, 1H) ), 4.05-4.00 (m, 4H), 3.70 (br, 1H), 3.55-3.48 (m, 6H), 3.38-3.28 (m, 2H), 2.81 (t, J=7.44 Hz, 1H), 2.72- 2.69 (m, 2H), 2.58 (t, J=7.72 Hz), 1.61-1.60 (m, 1H), 1.54-1.51 (m, 1H), 1.33 (m, 4H), 1.23-1.17 (m, 1H) , 1.13 (t, J = 7.08 Hz, 3H). Example 209: {4-[(3·{[2-(cyclohexylsulfanyl)-4-oxo-3-[(2R)-tetrahydrofuran- 2-ylmethyl]-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)·yl]carbonyl}azetidin-1-yl)methyl] Manufacture of methyl phenyl}acetate (2E)-but-2-enic acid ester [Chem. 103]

The ethyl acetate solution (8 mL) of Example Compound 135 (200 mg) was warmed to 40 &lt;0&gt; Keep it at 4 〇. After stirring for 1 hour, the mixture was allowed to cool to room temperature over 4 hours, and then cooled to 0 ° C in an ice bath and stirred for 1 hour. Then, the crystallization of the crystallization was carried out under reduced pressure at room temperature overnight to obtain the compound of Example 209 (195 mg) &lt;RTI ID=0.0&gt;&gt; m, 4H), 6.64 (s, 2H), 4.28 (s, 1.2H), 4.28-4.19 (m, 1H), 4.10 161077.doc -196· 201245190 (S, 0.8H), 4.17-3.90 (m, 2H), 3.90-3.77 (m, 2H), 3.77-3 71 (m, 1H), 3.71-3.58 (m, 9H), 3.58-3.43 (m, 3H), 3.34.3 25 (m, 2H), 2.67-2.52 (m, 2H), 2.11-2.01 (m, 2H), 2.01-1 89 (m, 2H), 1.89- 1.78 (m, 1H), 1.78-1.63 (m, 3H), 1.63-1.26 • (m, 6H).

• mp : 119 °C ^ XRD : 2Θ=5.3, 6.2, 6.9, 8.5, 9.5, 1〇5, 13 j, 13 8 , 14.5, 15.0, 15.8, 16.9, 18.2, ΐ9·〇, 2〇2, 22 〇, 23 〇, 27.4 ' 32.3 ' 37.3 Furthermore, in the X-ray diffraction (XRD) measurement, the X-ray diffraction system X'pert MPD (PANAlytical) is used, and the anode material is copper and K Alphai is 1.54 A. Voltage 45 kV, current 40 mA, starting angle (2 Θ) 4. End ^ (2Θ) 40°, step size (2Θ) 0.017. And measure at a time of 1〇〇 3 per step. Specifically, a non-reflective Si plate was used as a measurement sample plate, and a measurement sample of about 5 mg was applied to a non-reflective Si plate, and the measurement was carried out under the above-described measurement conditions. The following X-ray diffraction measurements were also carried out in the same manner. Examples 210 to 213: . . . The compounds of the above examples (Examples 65, M2, ^ and _ ' were synthesized according to the method of Example 2G9. The compounds of Examples 2i() to 2i3 were synthesized. ] 〇〇

161077.doc -197- 201245190 [Table 6] Example No. Ri R3 Ή-NMR spectrum, melting point and XRD 210 Ή-NMR (400 MHz, DMSO-cU): 6{p pm) = 7.56-7.53 (m, 3H) , 7.31-7.2 9 (m, 2H), 7.19-7.16 (m, 4H), 6.6 0 (s, 2H), 4.27 (s, 1.5H), 4.08 (s, 0.5H), 4.06-4.00 (m, 2H), 3.76-3 .44 (m, 10H), 2.84-2.79 (m, 2H), 2.64-2.56 (m, 4H), 1.96-1.94 (m, 2H), 1.60-1.51 (in, 3H), 1.38-1.29 (m, 4H), 1.23-1.15 (m, 4H). mp: 156°C XRD: 2Θ= 4.5, 9.0, 10.1, 11.4, 1 1.7, 13.8, 14.5, 15.4, 16.0, 17.6, 18.3, 18.7, 19.2, 20.3, 20.9, 21. 4, 22.6, 24.1, 24.7, 30.1 211 Me Me〇2C^XX/ Ή-NMR (400MHz, DMSO-de): δ(ρ pm)= 7.44-7.42 (m, 2H), 7.37-7. 34 (m, 1H), 7.26-7.18 {m, 5H), 6.60 (s, 2H), 4.29-4.28 (m, 1.3 H), 4.11-4.10 (m, 0.7H), 3.81-3. 48 (m, 13H), 3.38-3.32 (m, 2H), 2.67-2.63 (m, 2H), 2.00-1.91 (m, 5H), 1.60-1.50 (m, 3H), 1.33 (br , 4H), 1.23-1.20 (m, 1H). mp: 116°C XRD: 2Θ= 5.0, 6.2, 8.3, 10.3, 12. 8, 14.2, 15.0, 15.3, 16.3, 17.2, 1 8.1, 19.9, 21.8 212 iH-NMR (400MHz, DMSO-de): δ(ρ pm)= 7.54-7.53 (m, 3H), 7 .32-7.2 9 (m, 2H), 7.23-7.20 (m, 4H), 6.6 0 (s, 2H), 4.27 (s, 1.2H), 4.09 (s, 0.8H), 3.74-3.44 (m, 13H), 3.31-3.27 (t, J = 7.32 Hz, 2H), 2.69-2. 60 (m, 2H), 1.94 (br, 2H), 1.60-1 .50 (m, 3H), 1.35-1.31 ( m, 4H), 1 .20 (br, 1H). mp: 132°C XRD: 2Θ= 5.2, 6.1, 8.6, 10.2, 12. 3, 14.5, 15.8, 17.0, 17.7, 19.2, 1 9.4, 20.3, 21.3, 22.1, 23.8, 25.0, 26.2, 27.6, 30.4 161077.doc -198- 201245190 213

JO

MeQ2C

Ή-NMR (400MHz, DMSO-de): 6(p pm) = 7.54-7.53 (m, 3H), 7.32-7.2 7 (m, 3H), 7.18-7.12 (m, 3H), 6.6 0 (s, (2, H) -1.91 (m, 2H), 1.60-1.51 (m, 3H), 1.35-1.31 (m, 4H), l. 23-1.19 (m, 1H). mp: 146°C XRD: 2Θ= 4.9, 9.8, 11.6, 14.2, 1 6.0, 16.4, 17.0, 17.5, 18.1, 18.9, 19.6, 20.8, 21.1, 21.5, 22.0, 23. 2, 23.4, 24.0, 24.5, 25.9_ Examples 214~216: Example 214 In the step (r4-ii), a compound synthesized using 3-butoxyphenol is used instead of cyclohexylamine, and in addition to the reference example 4, according to the step (xi) to (xii) of the embodiment 17, the reference example 3, followed by synthesis according to Example 19. In Examples 215 and 216, the corresponding ester compounds of Example 95 and Example 2 14 were respectively used and synthesized according to the method of Example 2. [化105]

199-161077.doc 201245190 [Table 7] Example No. R3 Ή-NMR spectrum or MS spectrum 214 iH-NMR (400 MHz, CDCI3): 6 (ppm) = 7.59-7.42 (m, 3H), 7.38-7.18 (m , 5H), 6.92-6.82 (m, 2H), 6.18-6.73 (m, 1H), 6.68-6.56 (m, 2H), 4.60 (s, 2H), 4.51 (s, 0.8H), 4.26 (q, J = 7.0 Hz, 2H), 4.19 (s, 1.2H), 3.91 (t, J = 6.5Hz, 2H), 3.872-3.78 (m, 1H), 3.78-3.57 (m, 5H), 3.57-3.55 ( m, 3H), 2.55 (br, 2H), 1.80-1.69 (m, 2H), 1.53-1.40 (m, 2H), 1.29 (t, J = 7.0Hz, 3H), 0.96 (t, J = 7.0Hz , 3H). 215 M + H+ = 623 216 M + H+ = 639 Pharmacological test The pharmacological action of a representative compound of the present invention was investigated. Test Example 1: (1) Preparation of human MGAT2 recombinant protein The human MGAT2 recombinant protein was prepared by introducing a human MGAT2 gene described in the literature (American Journal of Physiology, 285, E927-E937, 2003) into a cell line. (2) Human MGAT activity assay (assay-1) (Condition A) A DMS0 solution containing a test compound of a specific concentration of 2 pL was added to a 2.0 mL microcentrifuge tube. To this tube was added 22 mM Tris (tris) containing 0.88 mg/mL BSA, 2.3 mM MgCl2, 60 μM 14C-Delta-CoA (GE Healthcare) and 1.59 mg/mL (diluted according to specific activity) human MGAT2 recombinant protein. (hydroxymethyl)aminomethane hydrochloride, tri-methylaminomethoxonate hydrochloride solution (pH 161077.doc -200- 201245190 7.4) 198 μί 'incubated at 37 ° C for 5 minutes. After 5 minutes, 25 μM (in terms of final concentration) of monoolein 2 was added to the tube and then incubated at 37 for 5 minutes. After 1 minute, 167 mL of isopropyl alcohol was added to the tube, and 1.35 mL of MicroScintTM-E (Perkin Elmer) was added, and after shaking again, the radioactivity was quantified. (Condition B) A dmSO solution containing 2 μί of a specific concentration of the test compound was added to a 2.0 mL microcentrifuge tube. A 28 mM Tris solution (pH 7.4) containing 1 mg/mL BSA, 3.1 mM MgCl2, 24 μΜ 14C-palm 醯-CoA ((3E Healthcare) and 12.8 pg/mL human MGAT2 recombinant protein was added to the tube. 196 μί, at 37. (: 5 minutes under heat. After 5 minutes, add 2 5 monoolein 2 μί ' to the tube at a final concentration of 25 μΜ and then incubate for 5 minutes at 37 t. 1 After 〇 minute, 0.167 mL of isopropyl alcohol was added to the tube, and then 35 mL of MicroScintTM-E (Perkin Elmer) was added, and after shaking again, the radioactivity was quantified.

The radioactivity quantified by (Condition A) or (Condition B) was taken as mg AT activity. When the MGAT activity when the DMSO solution was added was set to A, and the MGAT activity when the test compound was added was set to B, the inhibition rate of the test compound was calculated as 八八(7)/以卜丨(9)(9)^ The inhibition rate was calculated at a plurality of concentrations, the addition concentration was set to X, and the inhibition rate was set to γ, and the approximate expression: Y=100/(1+exp{_s*[1〇g(x)_1〇g(4)(1) was obtained. 〇0/〇 suppression concentration a (here, s represents the slope of the bending point). The 50% inhibition concentration a obtained by this is described as IC5〇 in Table 8. I61077.doc •201 - 201245190 [Table 8 Example No. ICso (μΜ) 15 0.33 17 0.013 18 0.41 27 0.48 30 0.33 31 1.5 35 0.38 38 0.13 39 0.13 49 0.73 56 . 0.014 58 2.8 62 0.23 65 0.0041 67 0.22 70 0.20 75 0.045 76 0.053 85 0.034 (3) Human MG AT activity assay (assay-2)

A DMSO solution containing 2 μί of a specific concentration of the test compound was added to a 2.0 mL microcentrifuge tube. A 28 mM Tris solution (pH 7.4) containing 1.1 mg/mL BSA '3.1 mM MgCl2 '26 μΜ 14C-Brown-CoA (Perkin Elmer), 12.8 pg/mL human MGAT2 recombinant protein was added to the tube. pL, incubated at 37 ° C for 5 minutes. After 5 minutes, 2.5 mM of monoolein 2 μιη was added to the tube and then incubated at 37 ° C for 5 minutes. After adding 0.2 mL of isopropanol/heptane (4:1) to the tube and stopping the reaction, 0.4 mL of heptane was further added and uniformly mixed. After centrifugation, the upper layer was recovered and 150 μί of ethanol/0.1 N NaOH/H 2 O (50 : 5 : 45) was added and mixed. After centrifugation, the upper layer was recovered, and 500 μM of EcoscintTM 161077.doc -202 - 201245190 0 (National Diagnostics) was added and shaken, and radioactivity was measured as a MGAT activity using a liquid scintillation counter (Hitachi-Aloka Medical). In the same manner as in the above (2) (measurement method-1), the compound concentration IC50 at which the enzyme activity was inhibited by 50% was determined from the MGAT activity when a compound having a plurality of concentrations was added, and the results are shown in Table 9. [Table 9] Example No. ICso (μΜ) 31 2.1 38 0.18 39 0.28 65 0.0047 70 0.23 76 0.082 85 0.061 87 0.027 88 0.017 89 0.041 95 0.0078 96 0.034 97 0.0058 98 0.0024 99 0.0078 100 0.0081 101 0.0067 102 0.008 7 103 0.011 104 0.13 106 0.047 109 0.13 .111 0.11 114 0.0090 115 0.29 118 0.010 119 0.0076 121 0.11 122 0.029 123 0.0055 Example number ICso (μΜ) 127 0.28 130 0.014 132 0.48 135 0.0057 139 0.0076 140 0.014 142 0.019 143 0.016 146 0.010 147 0.65 149 0.0042 150 0.0060 151 0.0063 152 0.0028 153 0.0072 154 0.041 156 0.76 165 0.11 166 0.28 168 0.33 169 0.39 171 0.18 192 0.17 200 0.11 201 0.21 202 0.16 203 0.0092 205 0.020 206 0.033 161077.doc -203 - 201245190 Test Example 2: Small intestine The fat absorption inhibiting effect &quot;T confirms the fat absorption inhibition effect of the bicyclic mouth bite compound of the present invention in the small intestine by the following manner. Mice (ICR, 8-9 weeks old, male rats, japan SLC) were fasted overnight (about 24 hours) 'suspend test compound (eg 3 〇mg/kg) in 5% thiol cellulose (MC) solution The mice are administered to the mice (in addition, the MC solution can also be diluted with a concentration of MC liquid such as 〇5〇/〇, and used instead of 5% gum arabic, etc.). After 10 minutes, Intralipid 20% (Terumo) (10 mL/kg) was administered by forced oral administration (this time point was set to ο minutes). Blood was collected from the tail vein (〇hr, 1 hr, 2 hr '3 hr, 4 hr), and the concentration of triglyceride (TG) in plasma was determined using triglyceride E-Test Wako (Wako Pure Chemical Industries, Ltd.). Variety. The effect of inhibiting the increase in plasma TG by the test compound was confirmed by the above method 'by comparison with the change in plasma TG of the solvent administration group'.

From the above results, it is understood that the compound of the present invention has an effect of acting as a MGAT-inhibiting agent and can be expected as a prophylactic and/or therapeutic agent for MGat-related diseases. [Industrial Applicability] The bicyclic pyrimidine derivative of the present invention and a physiologically acceptable salt thereof have MGAT inhibitory action and can be used as an obesity, metabolic syndrome, hyperlipidemia, hyper-slipemia, and high Prophylactic and/or therapeutic agents for VLDL, hyper-fatty acidemia, diabetes, and atherosclerosis. 161077.doc •204·

Claims (1)

201245190 VII. Patent application scope: 1 _ A bicyclic bite compound represented by formula (I) or a physiologically acceptable salt thereof, [Chemical 1] 0 Wherein R represents a hydrogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower cycloalkyl group which may be substituted, a lower cycloalkenyl group which may be substituted, a phenyl group which may be substituted a substituted naphthyl group or a substituted saturated or unsaturated heterocyclic group, R represents a hydrogen atom, a lower alkyl group which may be substituted, a lower alkyl group which may be substituted, a lower alkynyl group which may be substituted Substitutable lower cyclic ring, substituted lower cycloalkenyl, substituted lower alkyl fluorenyl, substituted phenylcarbonyl, substituted phenyl, substituted naphthyl or a substituted or unsaturated heterocyclic group, R3 represents a hydrogen atom, a substituted alkyl group, a substituted alkenyl group, a substituted alkynyl group, a substituted lower cycloalkyl group, a substituted lower cyclyl, a substituted phenyl group, a substituted naphthyl group or a substituted saturated or unsaturated heterocyclic group, wherein R3 is not a benzamidine group, and R4 and R5 are independently Represents a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, and may be substituted C3 6 cycloalkyl, hydrazine H or hydrazine R4b (wherein 161077.doc 201245190 R4b represents a substituted C1-6 alkyl group or a substituted C3-6 cycloalkyl group), X represents a halogen atom, sulfur Atom, _N(R6)-4_C(R7)(R8)- (wherein R6 represents a hydrogen atom, a lower alkyl group which may be substituted or a substituted base group' or R2 and R6 may together form a cyclic amine And R7 and R8 each independently represent a hydrogen atom, a functional atom, a lower alkyl group which may be substituted, a C3.6 cycloalkyl group which may be substituted or a substituted phenyl group, or R7 and a ruler 8 may be used together. Forming a cycloalkyl ring), Y represents any one of the following formulas (II), (III), (IV) or (V): [Chemical 2], &amp; father and R (&quot;) (&quot;丨)(丨V) (V) (wherein R9 represents a hydrogen atom, a lower alkyl group which may be substituted, a lower cycloalkyl group which may be substituted, a substituted phenyl group or a substitutable salt Or an unsaturated heterocyclic group, Z represents an oxygen atom or a sulfur atom), m represents 1, and η represents 2J. A bicyclic pyrimidine compound or a physiologically acceptable salt thereof, wherein the bicyclic pyrimidine compound is represented by the formula (Ia): (la) 16l077.doc 201245190 [wherein each symbol is as defined in claim 1 and 3, such as the bicyclic hydroxyl compound of claim 2 or a physiologically acceptable salt thereof] wherein R1 represents the following formula (2a,), (2 (four), (10) or (as in the case of the person - the base shown: [Chemical 4] Ra2a, Ra2b, Ra2c, Hanshan, Rb2, 尺 and Han 独立 independently represent a hydrogen atom, a halogen atom, a CF3, a CN, an OH, a Ci 6 alkyl group, a Ci6 alkoxy group (here 'the C. 6. alkane The base and c!-6 alkoxy group may be substituted by CO 2 H or CO 2 CRlgl Rlg 2 R ^ 3 (here, Rui, R! g 2 and R 1 3 are each independently represented by a hydrogen atom, C, · 4 alkyl group (the group may be via 〇H, Cm alkoxy, C3.6 cycloalkyl which may be substituted by C, .4 alkoxy, saturated heterocyclic group of 5 or 6 members, saturated heterocyclic oxy group of 5 or 6 members, or NR1blRlb2 substituted, Rlbl and Rlb2 each independently represent a hydrogen atom or an alkyl group), a C3.1 anthracenyl group (the group may be substituted by 1 to 2 substituents selected from a fluorine atom and a Ci-4 alkoxy group), 161077.doc 201245190 a C6-1G aryl group (which may be substituted by a _ atom or a Ci 4 alkoxy group), a 5- or 6-membered saturated heterocyclic group, or a heteroaryl group of 5 to 10 members (the group may be cw-alkyl) a group or a CM alkoxy group, or RW and RW may form a 3 to 8 membered cycloalkyl ring or a 5 or 6 membered saturated heterocyclic ring or a Cu alkane with the carbon atom to which the bond is bonded. Carbocarbonyl, C02Ru, NRibRu or c (=〇)NRldR|e, and as long as it is chemically acceptable, it can be substituted at any position and Ra2a, Ra2b, Ra2c, Ra2d, ruthenium, and η are hydrogen atoms, CF3, CN, C|_6 a group, c "Hyperyl group, C02Rla, NRibRu or c (= 〇) NRldRle, Rla, Rlb, R1., W and Rle each independently represent a hydrogen atom or a C group, or P and or Rld and Rle It is also possible to form a cyclic amine group or a morpholinyl group of 4 to 8 members with these respective linkages = N, and Rd2e and R, independently of each other, and having a plurality of groups, represent an ammonia atom, 〇H, C |·...1-- alkoxy or phenyl (here, the phenyl group may be substituted by a halogen atom, CF3, C|alkyl, co2H, c〇2_Ci 6 alkyl or Ci 4 alkoxy) Or 'may also form a 3 to 8 membered cycloalkyl ring with a carbon atom, or 'bonded to a carbon atom adjacent to a carbon atom via 〇~3 carbon atoms. The two carbon atoms bonded and the carbon chain between the carbon atoms together form a 4- to 8-membered cycloalkyl ring, X, an oxygen atom or a na, (wherein RC2 represents a hydrogen atom or c"i. J6I077.doc 201245190 (院)), ^ represents an oxygen atom or a sulfur atom, n2a, n2b, p2c, p2d, n2f and one represents an integer of 〇~4, n2c represents an integer from 1 to 6, m2d represents an integer from 1 to 3, and n2d represents 0. An integer of ～3, n2e represents an integer of 0 to 8]; R2 represents a group represented by any one of the following formulas (3a), (3b), (3c), (3d) or (3e): ] [wherein, Ra3a, Ra3b, Ra3e, Ra3d &amp; Rb3 each independently represent a hydrogen atom, a halogen atom, a CF3, a CN, an OH, a Cm alkyl group, a Cl.6 alkoxy group (the group may be via a Ci.4 decyloxy group) Substituting), Cu-based thiol, c〇2R2a, NR_2bR2c or C(=〇)NR2dR2e, and may be substituted at any position for a plurality of Ra3a χ j^a3b χ Ra3c^Ra3d , Rh as long as it is chemically tolerable R2b, R2c, R2d and R2e each independently represent a hydrogen atom or CM. 161077.doc 201245190 The base or the heart may form a cyclic amine group of 4 to 8 members with the respective N groups, and X3d represents an oxygen atom, a sulfur atom or an N (RC3M formula, an atom or C丨·丨〇 基 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n n Indicates an integer of 〇~8]; R3 represents a group of the following formula (4g), (4h) or (4i) [wherein, Arm represents a stupid or heteroaromatic ring, and R 8 and the ruler h each independently represent a hydrogen atom, a south atom, (3), CN, 〇H, Cl, an alkyl group, a cycloalkyl group, a C, -6 alkane. Oxy, c3_6 cycloalkoxy 'Cl·6 alkylcarbonyl, C02R3aa, NR3abR3aC, 161077.doc 201245190 C(=〇)NR3adR3ae or CH=CH-RW (wherein R3aa, R3ab, R3ac, Han... and ruler 3^ independently represents a hydrogen atom or a C|house group or a group of -6 and C and 〇 can form a cyclic amine group of 4 to 8 members together with these respective bonded n; representing CN, c〇2H, c 〇 2R Chuan or C (= 〇) NR3f2R3f3, W, R3 &quot; and R3. Each independently represents a hydrogen atom or c].6 appearance base), m chemically acceptable, then can replace a plurality of Ra4g & amp at any position Ra4h, Rd4g and Re4g, R d4h Re4h, Rf4h and R k4h RMh, Rh4h, Ri4h, Rj' and Rd4i, Re4i, R(4) and Rg4i are independent of each other and have a plurality of groups independently representing hydrogen atoms, 〇H, CN6 alkyl, C〇2H, C (VCi 6 pit base, ^ 6 oxime or base (here, the phenyl group can be halogen atom, CP〗, 匸 4 alkyl, C 〇 2H COyC^·6 alkyl or c1-4 alkoxy substituted), or Rd4g and R “g, Rd4h and Re4h ' Rf4f^Rg4h, ruler _ and R, 4h, Rj4lRk4h, Rd4i and Re4i, and Rf4jRg4i respectively Forming a 3 to 8 membered cycloalkyl ring or a 5- or 6-membered saturated heterocyclic ring together with one of the carbon atoms bonded thereto, or bonding to a carbon atom adjacent to each other via 〇 to 3 carbon atoms The two R "g, Rd4h, Rf4h, Rh4h, Rj4h, Rd4, Rf4i may also form a 4 to 8 membered cycloalkyl group together with the two carbon atoms bonded thereto and the carbon chain between the carbon atoms. The ring, n b4h jr p b4i , independently represents a group represented by any one of the following (i) to (xi): (0 hydrogen atom, I61077.doc 201245190 (ii) dentate atom, (iii OH ' (iv) OR3bl, (v) CN, (vi) C02H, (vii) C(=0)NR3b2R3b3, (viii) S〇2NR3b4R3b5, (ix) NR3eC(=〇)NR3b6R3b7, (here, R3bl Represents an argon atom R3b2, R3b3, R3b4, R3b5, Cl.IQ alkyl or alkanoyl; i3b6, R3b7 and R3e each independently represent a hydrogen atom or a Cmq, or R3b2 and R3b3, R3b4 and R3b5, or R3b6 and R3b7 may also form a cyclic amino group of 4 to 8 members together with these respective bonded N groups, and (X) any one represented by the following formula (4f): [Chemical 7] ΟΗ 〇 II 0 0 II , containing, ΝΗ 2 (4f) (herein, 'R3 f represents a hydrogen atom or a Ci-1G 炫), or (xi) C02CR3glR3g2R3g3 (here, R3gl, R3g2 and R3g3 each independently represent a hydrogen atom, Ci-4 Alkyl group (this group may be OH, Cw alkoxy, C3.6 cycloalkyl which may be substituted by C!.4 alkoxy 161077.doc 201245190, a 5- or 6-membered saturated heterocyclic group, 5 members or 6-membered saturated heterocyclic oxy group, or NR3bSR3b9 substituted, R3bS and R3b9 each independently represent a hydrogen atom or a Cl 丨 Q alkyl group), a cycloalkyl group (the group may be selected from a fluorine atom and a C 4 alkoxy group) 1 to 2 substituents in the group are substituted), C6-l0 aryl (the group may be substituted by a halogen atom or a Cl. 4 alkoxy group), a saturated heterocyclic group of 5 or 6 members, or 5 members~ a 10-membered heteroaryl group (the group may be substituted by a Cn4 alkyl group or a Cm alkoxy group), or 'R3gl and R3e2 may form a 3 to 8 membered cycloalkyl ring together with the bonded carbon atoms, Or a saturated heterocyclic ring of 5 or 6 members, m4g represents an integer of 〇~1〇, m4h, n4h, p4f^q4h, and claws... and / respectively represent an integer of 〇~5, rh, s4h&amp S41 independently represents 〇 or i (where 'm4h represents an integer from 1 to 5 when r4h is 1, and 'm4i represents an integer from 1 to 5 when 8 to 1'; and n4h is 0. In the case where 'Rb4h denotes a base that is not in any of the above (1), (vii), (viii), (χ) or (χί); in the case where one is 1 and n4i is 〇, RMi means the above (〇 a group represented by any one of (vii), (viii), (χ) or (xi)]. 4. The bicyclic pyrimidine compound of claim 3 or a physiologically acceptable salt thereof, wherein R1 A group represented by any one of the following formulas (2a,), (2b.), (2c,), (2d'), (2e'), or (2g'): [Chemical 8] 161077.doc • 9 - 201245190 Ra a, Ra 2b, Ra 2 c, Ra 2 d, R b 2 and Ra 2 g * independently represent a hydrogen atom, a dentate atom, a CF 3 , a C w alkyl group, or a Cl 6 alkoxy group (here, the CK 6 alkyl group and the cK 6 alkoxy group) It can be substituted by c〇2H4 c〇2CRigiRig2Rlg3 (here, 'RW, Ru2 and RU3 each independently represent a hydrogen atom or a 匚!.4 alkyl group (this group can be saturated by OH, Cw alkoxy, 5 or 6 members) a heterocyclic group or NR1blRlb2 substituted, Rlbl&amp;Rm each independently represents a hydrogen atom or C丨·6 alkyl))), and as long as it is chemically acceptable, it can be substituted at any position to replace a plurality of scales, Ra2b, Ra2c , 尺山和尺..., R _ and R are independently of each other and have a plurality of groups independently representing a hydrogen atom, C, _6 alkyl group, Cl. 6 alkoxy group or phenyl group (here, the benzene) The base may be substituted by a dentate atom, CF3, C丨.4 alkyl or C丨-4 alkoxy), or 'R仏 and R may also form a 3~8 together with one of the carbon atoms bonded thereto a cycloalkyl ring, or a bond to a carbon atom adjacent to a carbon atom via 〇~3 carbon atoms, or between the two carbon atoms bonded to the carbon atom and the carbon atom „To form a ring-base ring of 4 to 8 members together,” means an oxygen atom or seven (8)^ in the formula ... represents a hydrogen atom or ~ 161077.doc 201245190 alkyl), 乂28 represents an oxygen atom or a sulfur atom, n2a, n2b, P, P and n2g represent integers of 〇~4, n2c represents an integer of 1 to 6, m2d represents an integer of 1 to 3, n2d represents an integer of 〇~3, n2e represents an integer of 1 to 6]; R2 represents the following formula The base of any one of (3a), (3c), (3d) or (3e): no [chemical 9] (3c) (3d) (3β) [wherein, R, Rdc, ..." and Rb3 K independently represent a wind atom, a dentate atom, a CF3, a Cl.6 alkyl group, or a Ck6 alkoxy group (this The group may be substituted by a oxy group, and may be substituted at any position as long as it is chemically tolerable, Ra3a, Ra3c and Ra3d, and Re3 means hydrogen X represents an oxygen atom, a sulfur atom or a ruthenium (Κ&lt;:3) (wherein atom or Cw alkyl), 161077.doc -11 - 201245190 1133 represents 0" integer, n3c represents an integer of U, m3d represents an integer from 1 to 3, n3d represents an integer from 0 to 3, and n3e represents 0 An integer of ～8; R3 represents a group represented by any one of the following formulas (4g), (4h), or (4i) [10] Wherein Arm represents a benzene ring or a heteroaromatic ring, and Ra4g&amp;Ra4h independently represents a hydrogen atom, a halogen atom, a CF3, CN, 〇H, Cl_6 phenotype, CN6 alkoxy group, C〇2R3aa, C(=: 〇) NR3adR3ae 'R3aa' R3ad&amp;R3ae independently represents a nitrogen atom or a Cl.6 alkyl group; R3af represents C〇2H, C02R3fl or C(=〇)NR3f2R3f3, and R3fl, R3f2 and R3f3 independently represent a hydrogen atom or Cw base), and y, chemically tolerable' can replace a plurality of Ra4g and Ra4h at any position, Rd4me4g, RcMh, Re4h, Rf4h Rg4h, Rh4h R i4h Rj4h 161077.doc •12· 201245190 &amp; Rk4h, and Rd4i, Re4i, Rf4i, and Rg4i are independently of each other and have a plurality of groups independently representing a hydrogen atom, a C.6 alkyl group, a C02H or a C02-CK group, or a Rd4g and R" g, RW^Re4h, Rf4h&amp;Rg4h, ruler... and Ri4h, Rj4h and, R and Re4i, and Rf4j Rg4i may also form a cyclopentyl group of 3 to 6 members together with one carbon atom of each of these bonds. Rings, R 4h and Rb41 independently represent the following (m), (w), (vi) (vii) or The group shown by any one of (xi): (iii) OH, (iv) 〇R3bl, (vi) C02H, (vii) C(=0)NR3b2R3b3, (here, R3b丨 represents a hydrogen atom, C , · 6 alkyl or c 丨 · 6 alkyl fluorenyl; rW and R3b3 each independently represent a hydrogen atom or a Ci. 6 alkyl group, or R3b2 and R3b3 may also form a 5-member with these respective N-bonds~ 7 member of the cyclic amine group), (xi) C02CR3glR3g2R3g3 (here, R3M, R3g2 and RW each independently represent a hydrogen atom or a hydrazine "alkyl group (this group may be via 0H, Ci.4 alkoxy, 5 members or 6-membered saturated heterocyclic group or NR3b8R3b9 substituted, Hanchuan and (9) each independently represent a hydrogen atom or a Cu alkyl group), m4g represents an integer of 1 to 6, and ',,,,,, and The integer represents 整数~5 161077.doc 13- 201245190 integer, r4h, S4h and one respectively represent 〇 or 1 (wherein, when r4h is 1, m4h represents an integer of 2~5; In the case, m4i represents an integer of 2 to 5; when ^ and n4h are 〇, Rb44 shows * as shown in any of the above (vii) or (8); 2 is 1 and ^ is 0. Time table Wherein (vii) or (χ〇) is not a group; R and R each independently represent a hydrogen atom, a fluorine atom or a C,_6 alkyl group which may be substituted by a fluorine atom, and μ represents an oxygen atom. , sulfur atom, ·N(R6)_ or ·C(R7) (wherein R6 represents a hydrogen atom or a Ci 6 alkyl group which may be substituted by a fluorine atom, and independently represents a hydrogen atom or may be substituted by a fluorine atom Ci6 base). 77. The bicyclic pyrimidine compound of claim 3 or a physiologically acceptable salt thereof, wherein Y is a group represented by formula (II), (ΠΙ) or (IV): [Chemical 11], human and 0乂Re (,|) (III) (IV) [wherein, each symbol is as defined in the request item i]. 6. The bicyclic mouth bite compound of claim 5 or a physiologically acceptable salt thereof wherein γ is a group represented by formula (III): [Chemical 12] 161077.doc 201245190 (丨丨丨). 7. A bicyclic mouth-forming compound or a physiologically acceptable salt thereof, wherein R3 is a group represented by the formula (4g): [Chem. 13] R〇4g (4g) [wherein, Arm is a benzene ring or a ° bite ring, Ra4g represents a hydrogen atom, a halogen atom, CM, 〇n, C02H, CO C]. 4 alkyl, or CH=CH-R3af ( Wherein R3af represents (7) or (3) a, a pyridyl group, and R g and R g are independently of each other and have a plurality of groups independently representing a hydrogen atom, a Ci.4 dalyl group, a C02H, or a c〇2 -C1-4 alkyl group, m4g represents an integer of 1 to 3]. 8. The bicyclic pyrimidine compound of claim 3, or a physiologically acceptable salt thereof, wherein R3 is a group represented by formula (4h): 161077.doc -15- 201245190 [In the formula, Arm is benzene or. Ratio σ, ΓΗ#, 53⁄4 4h \ p and q respectively represent the integers of 〇~3 (where m4h+n4h+p4h+q4h are. When the integer of ~1〇 is in the case of 〆, one means 2 Or an integer of 3), and the remaining symbols are as defined in the claim 4]. 9. The bicyclic pyrimidine compound of claim 8, or a physiologically acceptable salt thereof, wherein: Ra4h is a hydrogen atom, a dentate atom, a CF3, a c6 alkyl or a Cw alkoxy group, and Rb4h is (vi) C02H, or (xi) C02CR3glR3g2R3g3 (here, R3gl, Rh2 and Rh3 each independently represent a hydrogen atom or a C alkyl group (this group may be saturated with 〇H, Cm alkoxy, 5 or 6 members) a heterocyclic group or NR3b8R3b9 substituted, and independently represents a hydrogen atom 4C!.4 alkyl)), Rd4h, R"h, Rf4h, Rg4h, Rh4h, Ri4h, Rj4h, and Rk4h are independent of each other, and have a plurality of groups When independently representing a hydrogen atom or a Ci.4 alkyl group, Rf4h and ... may also form a 3 to 6 membered cycloalkyl ring together with the bonded carbon atom, m4h is 1 or 2, 161077 .doc • 16- 201245190 n4h is an integer from 1 to 3, p4h, q4h, and, respectively, independently 〇 or 1 (where m4h is 2 when the case is 1,) 10. The bicyclic pyrimidine compound or a physiologically acceptable salt thereof according to any one of 6, 8 or 9, wherein Rb4h is (xi) C02CR3glR3g2R3g3 (here, R3 Gl, R3g2 and R3g3 are as defined in the claim 9). Table 11, wherein the bicyclic pyrimidine compound of claim 3 or a physiologically acceptable salt thereof, wherein R1 is a formula (2a') or (2b1) ) The base shown: [Chem. 15] [wherein, Ra 2a &amp; Ra 2b are each independently a hydrogen atom, a halogen atom, a Gy alkyl group or a C 1 —4 alkoxy group 'n2ln2b is 〇]° 12. The bicyclic pyrimidine compound of claim 3 or a physiologically acceptable a salt in which R1 is a group represented by the following formula (2c'): [Chemical 16] Eight n2c 161077.doc 17 201245190 [Formula t, then any R is a hydrogen atom or a fluorine atom (as long as it is chemically acceptable, it is intended to replace a plurality of such groups), p2, 〇, 112 &lt;: 1 to 4 Integer]. 13. The bicyclic pyrimidine compound of claim 3 or a physiologically acceptable salt thereof, wherein R1 is represented by the following formula (2d,) or (2g,): [wherein, Ra2d&amp;Ra2g is a hydrogen atom, X2d&amp;x2g is an oxygen atom, 卩2 (1 and 1^ are 1, 1112&lt;1 is an integer of 2 to 3, and Π is an integer of 〇~1]. The bicyclic pyrimidine compound of claim 3 or a physiologically acceptable salt thereof, wherein R1 is a group represented by the following formula (2e'): 161077.doc • 18 · 201245190 [In the formula, alkoxy, and in the case of a plurality of groups, independently, Rd2e&amp;Re2e are independently of each other, a hydrogen atom or a Ci.4 alkyl group, and 1126 is an integer of 2 to 4] . 15. The bicyclic pyrimidine compound of claim 3, or a salt thereof, wherein R2 is a group represented by the following formula (3c) or (3d): [Chem. 19] (3c) (3d) [The symbols in the formula are as shown in the definition of claim 4]. The bicyclic pyrimidine compound of claim 15 or a physiologically acceptable salt thereof wherein R2 is a group represented by the following formula (3c): Ra3c Pc) [wherein Ra3c is a hydrogen atom, and n3c is an integer of 4]. 17. The bicyclic pyrimidine compound of claim 16, or a physiologically acceptable salt thereof, wherein 113 &lt;: is 2 to 4. 18. A bicyclic pyrimidine compound according to the above item 3 or a physiologically acceptable salt thereof, wherein R2 is represented by the following formula (3a): 161077.doc • 19· 201245190 [Chem. 21] N3a (3a) is a hydrogen atom or a C 1-6 aerobic group which can be substituted by (: 丨-4 alkoxy group [wherein Ra3a is a j group 'n3, 0], and x is an oxygen atom. A bicyclic pyrimidine compound or a physiologically acceptable salt thereof, wherein X is a sulfur atom or _N(R6)_ (wherein R6 represents a hydrogen atom or a Cm alkyl group). A bicyclic pyrimidine compound or a physiologically acceptable salt thereof, wherein X is -NH-. 21. The bicyclic pyrimidine compound of claim 19, or a physiologically acceptable salt thereof, wherein X is a sulfur atom. The bicyclic pyrimidine compound of Item 3 or a physiologically acceptable salt thereof, wherein R4 and R5 are each a hydrogen atom. 23. The bicyclic pyrimidine compound of claim 4 or a physiologically acceptable salt thereof, wherein R1 is as follows Formula (2a,) or (2b,): [Chem. 22] Wherein R 23 and Ra 2b are each independently a hydrogen atom, a halogen atom, C. 4 alkyl 161077.doc • 20-201245190 or Cw alkoxy, 1123 and 1121) are 0], and the following formula (2c1) ): [Chem. 23] [wherein, Ra2e may be a hydrogen atom or a fluorine atom (as long as it is chemically permissible to replace a plurality of such groups), 戸2£: 0, 112 £: an integer of 1 to 4], Or the following formula (2d'): [Chem. 24] (2d,) [wherein, Ra2d is a hydrogen atom, X2d is an oxygen atom, 卩2£1 is 1, m2d is an integer of 2 to 3, and 112£1 is an integer of 0 to 1] 161077.doc 21 201245190 The base; R2 is the following formula (3c): [Chem. 25] [wherein, Ra3e is a hydrogen atom, and n3e is an integer of 2 to 4]; R3 is a formula (4h): [Chem. 26] Ra4h Arm is a benzene ring or a bite ring, the ruler (10) is a hydrogen atom, a halogen atom, a CFS, a Cl e alkyl group or a Cl. 6 alkoxy group, and Rb4h is a (xi) C02CR3glR3g2R3g3 (here, R3gl 'Rh and R3g3 are independent The ground represents a hydrogen atom or a C,·4 alkyl group (this group can be saturated by OH, C丨·4垸 其 其 、 ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca ca Or NR3b8R3b9 is substituted, R3»&gt;8&amp;R hydrogen atom or (^.4 alkyl)), Ri4h, Rj4h and Rk4h Rd4h, Re4h, Rf4h, Rg4h, Rh4h h are independent of each other, and there are multiple bases respectively Independently representing a hydrogen atom or a Cw alkyl group, or Rf4h may also form a 3 to 6 membered cycloalkyl ring together with the bonded carbon atoms, m is 1 or 2, and n4h is an integer of 1 to 3 , P4h, q4h, r4h and, respectively, are independently a group of 〇 or 1 (where m4h is 2 when ... is )); R4 and R5 are each a hydrogen atom, and X is a sulfur atom or _ NH_, y is the formula (in): [Chem. 27] (Hi) The base shown. The bicyclic pyrimidine compound of claim 1 or a physiological salt thereof, wherein the above bicyclic pyrimidine compound is selected from the group consisting of: {4·[(3-{[2-(cyclohexylsulfanyl)). 'oxo_3_phenyl·ms·tetrahydropyridinium[4'3-d]pyrimidine·6(4Η)-yl]carbonyl hydrazide arbutan-1-yl) A 161077.doc -23 - 201245190 benzyl]phenyl}acetate, (2Ε)-3-{4-[(3-{[2-(cyclohexylsulfanyl)_4_oxophenyl)-1-yl) fluorenyl ]phenyl}prop-2-enoic acid methyl ester, , ({4-[(3-{[2-(cyclohexylthioalkyl))-4-oxo_3_ cage 1&lt;; + _W7, 8-tetrahydroindene bite and [4,3 benzoate)-yl]alkyl}azetidinyl)methyl]benzyl}oxy)acetate, 4-(3-{[ 2-(cyclohexylthioalkyl)-4-oxo_3_phenyl_3,5,78_tetrahydroindole ratio bite [4'3-d] mouth bite-6(4H)-yl] Ethyl butyrate, ethyl butyrate, 4-[2-(3-{[2·(cyclohexylsulfanyl)-4_oxo·3_stupyl_3,5,7 , 8_tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl}indolyl)ethyl]benzoate decyl ester, 3-{4-[ (3-{[2-(cyclohexylthioalkyl)-4-oxo_3_ stupid · 3,5,7,8-tetraoxaacrid[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl)methyl]phenyl}propionate 曱S , 3_{4-[(3-{[2-(cyclohexylamino)-4-oxo_3_ stupyl_3,5,7,8 tetrahydroindolepyridyl[4,3-d] Pyrimidine-6(4H)-yl]carbonyl}azetidinyl}methyl)phenyl]propionate propionate, 6·(3-{[2·(cyclohexylthioalkyl)_4· Oxo _3_ stupyl_3,5,7,8-tetrahydroindolepyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl)hexanoic acid Ester, 4-[2-(3-{[2-(cyclohexylamino)-4-oxophenyl-3,5,78 tetrahydroindolepyridinium[4,3-d]pyrimidine-6 ( 4H)-yl]carbonyl}azetidinyl]indolyl)ethyl] 161077.doc • 24· 201245190 methyl benzoate, 3-{4-[(3-{[2-(cyclohexylthio) ))-4-oxo-3 J-benzyl-3,5,7,8-tetrahydroη ratio bite and [4,3-d] than -6(4H)-yl]yl} Butyrate small base) methyl]phenyl}propionic acid ethyl ester, 9-(tetra)2-(cyclohexylsulfanyl)-4-oxo-[4,3-d]__6(4H)-yl] }Azetidinated small base) ethyl decanoate, {3-[(3-{[2·(cyclohexylthioalkyl)_4_oxo_3_ stupyl_3,5,7,8- Four gas. Than and bite [4,3-d]t, 6__yl] alkene}azetidinyl)methyl]phenyl}acetate oxime, (3-[(3·{[2-( Cyclopentylthioalkyl) oxyoxyl I phenyl HUM acridine [4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl)methyl]phenyl}acetic acid Methyl ester, {3-[(3-{[2-(cyclohexylsulfanyl)-3-(3,3-difluorocyclobutyl)4oxo-3,5,7,8-tetrahydropyridine And [4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}acetic acid 曱g, {4-[(3-{[2 -(cyclopentylthioalkyl)_4_oxo_3-phenyl_3,5,7,8-tetraazolo[4,3-d]pyrimidin-6(4H)-yl]carbonyl}nitrogen Heterocyclobutane-fluorenyl-yl)phenyl]phenyl}acetate, 3-{4-[(3-{[2-(cyclohexylsulfanyl)-4)oxo-3-phenyl]3 ,5,7,8_tetrahydrogen ratio bite and [4,3_d]pyridin-6(4Η)-yl]carbonyl}azetidin-[yl]methyl]-2-phenylene}propyl Acidic vinegar, {4-[2-(3-{[2-(cyclohexylsulfanyl))-4_oxo_3_phenyl_3 5,7,8 tetrahydrogen. Bis-pyrene[4,3_d Pyrimidine -6(4Η)-yl]carbonyl}azetidin-4-yl)ethyl 161077.doc -25- 201245190 phenyl]phenyl}acetate, {4-[(3-{[2-( Cyclohexylsulfanyl)-4-代i laughing base-3,5,7,8-tetrahydro «pyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl) phenoxy Ethyl acetate, f {3-[(3-{[2-(cyclohexylsulfanyl)-4-oxo-3_^ + 丞-J,), /, 8-tetrahydropyrido[4] ,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl)methyl]phenoxy}acetate, hydrazine {4-[(3-{[2-(cyclohexyl)) Sulfur-based)-3_(3,3-difluorocyclobutyl)4oxo 3,5'7,8-tetrahydroindene bite [4,3-d]«-6 (called 基]县气Heterocyclic ketone-alkyl-1-yl) fluorenyl]phenyl}acetic acid 曱g, {4-[(3-{[2-(cyclohexylthioalkyl)_3_(3,3-difluorocyclobutyl) Oxygen 3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4η)-yl]carbonyl}azetidine|ytyl-1-yl)methyl]phenoxy}acetic acid乙,, 3-{4-[(3-{[2-(cyclopentylthioalkyl)_4_oxo_3_benzene]_3 5 7 _,, /, 8-tetrahydropyridine [4,3_d]pyrimidine_6(4Η)_yl]carbonyl}azetidine+yl]phenyl}propionic acid ethyl ester, A{4-[(3-{[2-(cyclopentyl)sulfide Alkyl)-4_oxo_3_phenyl-3,57 8 pyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidinyl _ κ4) fluorenyl Phenoxy}ethyl acetate {4-[(3-{[2-(cyclobutylsulfanyl))-4_oxo_3_phenyl_3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine· 6(4Η)_yl]carbonyl}azetidine-fluorenyl-methyl)phenyl}acetic acid decyl ester, 1-(4-[(3_{[2-(cyclohexylsulfanyl))_4_ Oxo-3 phenyl 3,5,7,8 tetrahydropyrido[4,3-d]pyrimidin 6(4Η)-yl]carbonyl}azetidinyl 4 161077.doc •26· 201245190 Methyl]phenyl}cyclopropanecarboxylate, {4-[(3-{[2-(cyclohexylsulfanyl)-4-oxo-3). Bispin-3-yl)_ 3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidin-1-yl)indolyl Phenyl} decyl acetate, '({5-[(3-{[2-(cyclohexylsulfanyl)-4-deutero-3-phenyl_3,5,7,8-tetraamine) Pyridyl[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl)methyl]»pyridin-2-yl}oxy)acetic acid decyl ester, {4-[( 3-{[2-(cyclohexylsulfanyl)-4-oxo-3·[tetrahydromethane-2-ylmethyl]-3,5,7,8-tetrahydropyrido[4,3 -d]pyrimidine_6(4Η)-yl]carbonyl}azetidin-1-yl)indenyl]phenyl}acetic acid (+/-)-methyl ester, {4-[(3-{[2 -(cyclohexylthioalkyl)·4.oxo-3-[(2R)-tetrahydro.fusin_2_ylmethyl]-3,5,7,8-tetrahydro- 0 ratio bite [4, 3-d] squeezing _6(4H)-yl]yl} azetidin-1-yl)indolyl]phenyl}acetic acid methyl vinegar, {4-[(3-{[2-( ring) Hexyl thiocarbyl)-4-oxo-3-[(28)-tetrahydrobital. 尚_2· mercapto]-3,5,7,8-tetrahydropyrido[4,3-(1 Pyrimidine -6(411)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}acetic acid, 3-{4-[(3-{[2-(cyclohexylsulfuric) ))-4-oxophenyl_3,5,7,8·tetrazo. ° ratio bite [4,3_d]pyrimidin-6 ( 4H)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}propanoic acid 2-methoxyethyl ester, 3-{4-[(3-{[2-(cyclohexylsulfuric) Alkyl)-4-oxo-3-3-styl_3,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl}azetidine_ Mercapto)methyl]phenyl}propionic acid 2-hydroxyethyl ester, {4-[(3-{[2-(cyclohexylsulfanyl)-3doffylmethyl)4oxo-3, 5,7,8-tetrahydrogen. Compared with bite [4,3-_bit, base m base] azetidin I61077.doc •27· 201245190 alk-1-yl)methyl]phenyl}acetate hydrazine Ester, {4-[(3-{[2·(cyclohexylsulfanyl)-3-(2-methoxyethyl)4_oxo-3,5,7,8-tetrahydropyridine And [4,3-d]pyrimidine_6(411)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}acetate 曱S, 6-(3-{[2-( Cyclohexylsulfanyl)-4-oxo-3-ylphenyl_3,5,7,8•tetrahydroacridazino[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}aza Cyclobutane·yl)decyl hexanoate, 4-[(3-{[2-(cyclohexylsulfanyl)-4-oxo-3-phenyl]-3,5,7,8-tetrahydroindole Bis-[4,3-(1]pyrimidin-6(411)-yl]carbonyl}azetidin-1-yl)indolyl] decyl benzoate, {4-[2-(3-{ [2-(cyclohexylsulfanyl)-4-oxo 3_phenyl_3,5 7 8•tetrahydroxantho[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidinyl)ethoxy]phenyl}acetic acid hydrazine Ester, {4-[(3-{[2-(cyclohexylsulfanyl)-4-oxo_3_(tetrahydrofuran_3_ylmethyl)-3,5,7,8-tetrahydrogen) Pyrido[4,3-d]pyrimidin-6(4H)-yl]carbonyl)azetidin-1-yl)methyl]phenyl}acetic acid methyl ester, {4-[(3-{[2 -(cyclohexylsulfanyl)-4-oxo_3_[(2r)_tetrahydrofuran-2-ylmethyl]-3,5,7,8-tetrahydro 0-bite [4,3-d] mouth Bite _6(4H)-yl] alkaloid}azetidin-1-yl)indolyl]phenoxy}acetic acid ethyl acetate, 3-{4-[(3-{[2-(cyclohexyl sulphide)炫基)-4-oxo_3_[(2r)_tetrahydrofuran-2-ylmethyl]-3,5,7,8-tetrahydro"pyrido[4,3-d]pyrimidine- 6(4H)-yl]carbonyl}azetidin-1-yl)methyl]phenyl}propionic acid ethyl acetate, {4-[(3-{[2-(3-butoxyphenoxy)oxy) )-4-oxophenyl-3,5,7,8-tetrahydrogen ratio bite [4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidin-butyl)曱161077.doc -28- 201245190 ethyl]phenoxy}ethyl acetate, {4-[(3-{[2-(3-butoxyphenoxy)-4-oxo-3-phenyl-) 3,5,7,8-tetrapyrido[4,3-d]pyrimidin-6(4H)-yl] Methyl}azetidin-i-yl)methyl]phenyl}methyl acetate, and {4-[(3-{[2-(cyclohexylsulfanyl)-3-[(2R)-2) -methoxypropyl propyl, 4,5,7,8-tetrahydropyrido[4,3-d]pyrimidin-6(4Η)-yl]carbonyl}azetidin-1-yl) Ethyl]phenyl}acetate. 25. A bicyclic pyrimidine compound represented by formula (lb) or a chemically stable salt thereof, [Chem. 28] Wherein P2 is a protecting group for an amine group, and represents a thiol group substituted with 1 to 3 phenyl groups (the phenyl group may be substituted with an oxime group of oxime) or (^-4 substituted by an alkyl group) =〇)〇RPi, or (C=0)Rp2, R represents a C1·4 alkyl group (the group may be substituted by 1 to 3 halogen atoms, wherein 'in the case where the group is a fluorenyl group' can pass 1~ 3 halogen atoms, phenyl or 9-diyl substituted) or alkenyl, Rp2 represents a hydrogen atom, Cm alkyl (the group may be substituted by u halogen atoms), wherein when the group is a Cw alkyl group, It may be substituted by 1 to 3 halogen atoms or C?·4 oxime) or phenyl, and R, R, R4, R5 and X are as defined in the claim 4] 161077.doc •29 - 201245190 26. A method for producing a bicyclic pyrimidine compound represented by the formula (id) or a physiologically acceptable salt thereof, [Chem. 32] (Id) [wherein, L is a leaving group' represents a halogen atom, or 〇s〇2Rl; here, the rl table may not be substituted by a C!·4 alkyl group or may be substituted by a c丨·4 alkyl group. Stupid base, Ρ 2 is as defined in claim 25, R1, R2, R3, R4, R5 and Χ are as defined in claim 4]; it includes the following two steps: Deprotection of the chemically stable salt of the formula (Ib), which is shown as a bicyclic pyrimidine compound or Obtaining a salt represented by the formula (Ic): a bicyclic pyrimidine compound or chemically stable thereof 161077.doc 201245190 Then it is reacted with a compound represented by the formula (Via): [Chem. 31] L _. 27. A method for producing a bicyclic pyrimidine compound represented by formula (Ie) or a physiologically acceptable salt thereof, [Chem. 36] [wherein, R3pl represents a group represented by any one of the following formulas (4gp), (4hp) or (4ip): [Chem. 37] M4gp represents an integer of 0 to 5, and m4hp&amp;m4ip* independently represents an integer of 0 to 4 (wherein, in the case where one is 1, m4hp represents an integer of 1 to 4; when 84| is 1, the m4ip An integer of 1 to 4), 161077.doc •31 · 201245190 R3P2 represents a hydrogen atom or a Ci-6 alkyl group, and P is as defined in the claim 25, R1, R2, R4, R5, X, Ann, Ra4g, Ra4h, Rb4h, Rb4i ' Ri4h . RJ4h ' q4h ' n4i &gt; r4h s4h and s41 are as defined in claim 4], which comprises the following two steps: a bicyclic pyrimidine compound represented by the formula (lb) of claim 25 or Its chemically stable salt is deprotected: [Chem. 33] Obtaining a bicyclic pyrimidine compound represented by the formula (Ic) or a chemically stable salt thereof: [Chem. 34] It is then reacted with a compound represented by the formula (Vlb): [Chem. 35] R3p1 〇 (Vlb) R3p2 28. A substituted azetidine compound represented by formula (VII) or its chemistry 161077.doc •32- 201245190 Sexually stable salt, [Chem. 38] Rb4h represents C〇2CR3glR3g2R3g3 (here, R3gl, R3g2 and R3g3 each independently represent a hydrogen atom, or a CM alkyl group (the group may be substituted by 〇H or CM alkoxy)), Rg4h, Rh4h, Ri4h, r4h , s4h, R4 and R5 are as shown in Arm, Ra4h, Rd4h, Re4h, Rf4h T?j4h pk4h w4h 4h 4h au Λ , K , m , n , p4h , q4h , as defined in claim 4 . 29. A method for producing a bicyclic pyrimidine compound represented by the formula (if) or a physiologically acceptable salt thereof, [Chem. 41] Rb4h is as defined in claim 28 161077.doc •33· 201245190 Arm, Ra4h, Rd4h, Re4h, Rf4h, RMh, Rh4h, Ri4h, Rj4h, Rk4h, m4h, n4h, p4h, q4h 'r4h and s4h, And Ri, R2, R4, R5 and X are as defined in the claim 4] comprising the steps of: substituting the azetidinium compound represented by the formula (VII) as claimed in claim 28 or its chemicality Stable salt: [39] (VII) reacting with a bicyclic pyrimidine compound represented by formula (VIII) or a chemically stable salt thereof: A pharmaceutical composition comprising the bicyclic pyrimidine compound according to any one of claims 1 to 24, or a physiologically acceptable salt thereof. A preventive agent and/or a therapeutic agent for a MGAT-related disease, which comprises the bicyclic pyrimidine compound according to any one of claims 1 to 24 or a physiologically acceptable salt thereof as an active ingredient. 3 2. An obesity, metabolic syndrome, hyperlipidemia, hyperlipidemia, • 34-161077.doc 201245190 Prophylactic agents for high VLDL, hyper-fatty acidemia, diabetes or atherosclerosis and/or A therapeutic agent which comprises the bicyclic pyrimidine compound according to any one of claims 1 to 24 or a physiologically acceptable salt thereof as an active ingredient. 0 161077.doc -35 - 201245190 IV. Designated representative figure: (1) The case The designated representative figure is: (none) (2) The symbol of the symbol of this representative figure is simple: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 161077.doc