JP4794200B2 - 4-amino-5-cyanopyrimidine derivatives - Google Patents

Description

  The present invention relates to pharmaceuticals, particularly 4-amino-5-cyanopyrimidine derivatives useful as adenosine A2a receptor agonists or pharmaceutically acceptable salts thereof and pharmaceuticals containing these compounds as active ingredients.

  Adenosine is a substance that exhibits various physiological actions by binding to receptors present on the cell surface. Adenosine receptors present on the cell surface belong to the family of G protein-coupled receptors and are classified as A1, A2a, A2b and A3. Among these, the adenosine A1 and A3 receptors are coupled to the Gi protein, and their activation reduces intracellular c-AMP levels. Adenosine A2a and A2b receptors are also coupled to Gs proteins and their activation increases intracellular c-AMP levels. Each of these four adenosine receptor subtypes has been cloned.

  Various studies have already been conducted on agonists and inhibitors that act on each of the adenosine receptor subtypes. These agonists and inhibitors have already been reported as therapeutic agents for cardiovascular disorders, ischemia reperfusion disorders, inflammation, Parkinson's disease, schizophrenia and the like. In particular, a number of adenosine derivatives have been reported as active ingredient compounds of adenosine A2a receptor agonists (see Patent Document 1-24).

  Furthermore, compounds that are structurally different from the above adenosine derivatives and do not have an adenine skeleton have also been reported as active component compounds of adenosine A1 or A2 receptor agonists. Specific examples thereof include a dicyanopyridine derivative (see Patent Documents 25-32). However, a cyanopyrimidine derivative having an action of activating the adenosine A2a receptor is not known.

  On the other hand, glaucoma is an intractable eye disease that affects all mammals including primates. Symptoms include blurred vision, pain, or loss of vision, loss of visual field due to optic nerve damage, and sometimes even blindness. The glaucoma is classified into high-tension glaucoma that is characterized by an increase in intraocular pressure (increased intraocular pressure) and normal-tension glaucoma that is not accompanied by increased intraocular pressure. Increased intraocular pressure in glaucoma results in an imbalance between the rate of aqueous humor secreted from the ciliary epithelium into the posterior chamber and the rate of aqueous humor drained and removed from the anterior chamber mainly via Schlemm's canal. As a result. This loss of balance is thought to be mainly due to an increase in the outflow resistance of the aqueous humor due to clogging of the discharge path of the aqueous humor. Glaucoma is a serious disease in which the number of patients is increasing year by year in advanced countries that are facing a super-aging society, and its social importance in the development of therapeutic agents is expected to increase further in the future.

  At present, in the treatment of glaucoma, control of intraocular pressure, which is the greatest risk factor, is the most important issue. Examples of such therapeutic agents include beta-blockers such as carteolol and timolol, such as latanoprost and isopropyl unoprostone. Prostaglandin derivatives such as carbonic acid dehydrogenase inhibitors such as dorzolamide are used. These drugs can act to regulate the production or excretion of aqueous humor and lower intraocular pressure.

  Adenosine A2a receptor agonists have a strong antihypertensive effect, and as described above, are reported to be effective as antihypertensive agents, therapeutic or preventive agents for ischemic diseases of the heart or brain, and antiatherosclerotic agents. In addition, it has also been reported to have an intraocular pressure lowering effect (see Non-Patent Documents 1 and 2).

  In addition, some research and development have already been conducted on adenosine derivatives having an intraocular pressure-lowering action (see Patent Documents 23 and 24).

However, when such an adenosine derivative is used as a therapeutic agent for glaucoma, there is a concern about a serious adverse effect that side effects on the central and cardiovascular systems are accompanied.
WO 01/027131 A1 WO 00/077018 A1 WO 00/078776 A1 WO 00/078777 A1 WO 00/078778 A1 WO 00/078779 A1 WO 00/072799 A1 WO 00/023457 A1 WO 99/67266 A1 WO 99/67265 A1 WO 99/67264 A1 WO 99/67263 A1 WO 99/41267 A1 WO 99/38877 A1 WO 98/28319 A1 US Patent No. 5877180 WO 00/044763 A1 WO 93/22328 A1 Japanese Patent Publication No. 1-333477 Japanese Patent No. 2774169 US Patent No. 4968697 JP 63-201196 Japanese Patent Laid-Open No. 2003-055395 JP 2002-173427 A WO 00/125210 A1 WO 02/070484 A1 WO 02/070485 A1 WO 02/070520 A1 WO 02/079195 A1 WO 02/079196 A1 WO 03/008384 A1 WO 03/053441 A1 J. Pharmcol. Exp. Ther. 320-326, 273 (1995) Eur. J. Pharmacol. 307-316, 486 (2004).

  As described above, an adenosine derivative having an adenine skeleton can be expected to be effective as an adenosine A2a receptor agonist, particularly as a therapeutic agent for glaucoma, etc. The action is insufficient. Moreover, these compounds have a fatal defect that they have side effects on the central and cardiovascular systems such as the strong blood pressure lowering action inherent in adenosine A2a receptor agonists based on having an adenine skeleton. Therefore, in place of these compounds, there is a demand in the art for the development of an adenosine A2a receptor agonist that can be used more safely, particularly a compound that can exert an intraocular pressure lowering effect that is effective as a therapeutic agent for glaucoma and the like.

  An object of the present invention is to provide a safer and more potent compound having adenosine A2a receptor agonistic action, which is required in the art.

  As a result of intensive studies to achieve the above object, the present inventors have succeeded in producing a certain 4-amino-5-cyanopyrimidine derivative, and the compound has an excellent adenosine A2a receptor agonistic action. Found the fact that it has. The present invention has been completed as a result of further research based on this knowledge.

  The present invention provides the compounds according to items 1 to 10 below.

  Item 1. General formula (1):

[Where
R ¹ represents a hydrogen atom, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a phenylcarbonyl group or a lower alkoxycarbonyl group.
R ² represents a lower alkylene group.
R ³ represents (1) a hydrogen atom, (2) a lower alkyl group, or any one of the following groups (3) to (12).

In the groups (3) to (12), R ⁴ is a lower alkylene group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ is a lower alkenylene group, R ⁷ is a lower alkynylene group, and R ⁸ is a lower alkyl group. Z ^{1 to} Z ³ each represent one of groups selected from the group consisting of the following (a1)-(a38), (b1)-(b8) and (c1)-(c22).

Z ¹ : (a1) lower alkyl group, (a2) aryl lower alkyl group, (a3) aminoaryl lower alkyl group, (a4) aryl lower alkenyl group, (a5) heteroaryl lower alkyl group, (a6) heteroaryl lower Alkenyl group, (a7) heteroarylaryl lower alkyl group, (a8) hydroxy lower alkyl group, (a9) aryloxy lower alkyl group, (a10) amino lower alkyl group, (a11) aminocarbonyl lower alkyl group, (a12) Lower alkylcarbonyl group, (a13) lower alkoxy lower alkylcarbonyl group, (a14) amino lower alkylcarbonyl group, (a15) arylcarbonyl group, (a16) aryl lower alkylcarbonyl group, (a17) aryl lower alkenylcarbonyl group, a18) aryloxy lower alkylcarbonyl group, (a19) heteroarylcarbonyl group, (a20) heteroaryl lower alkylcarbonyl group (A21) heteroaryl lower alkenylcarbonyl group, (a22) heteroaryloxy lower alkylcarbonyl group, (a23) heteroarylsulfanyl lower alkylcarbonyl group, (a24) heteroarylarylcarbonyl group, (a25) arylsulfanyl lower alkylcarbonyl group Group, (a26) arylcarbonyl lower alkylcarbonyl group, (a27) arylamino lower alkylcarbonyl group, (a28) lower alkoxycarbonyl group, (a29) lower alkylsulfonyl group, (a30) arylsulfonyl group, (a31) heteroaryl A sulfonyl group, (a32) a hydrogen atom, (a33) a lower alkyl group having a saturated heterocyclic ring, (a34) a carbonyl lower alkyl group having a saturated heterocyclic ring, (a35) an aryl lower alkyl group having a saturated heterocyclic ring, (a36) A carbonyl group having a saturated heterocyclic ring, (a37) a lower alkyl group having a saturated heterocyclic ring Alkylsulfonyl group, (a38) an arylcarbonyl group having a saturated heterocycle.

  The amino group constituting a part of each group described in the above (a3), (a10), (a11) and (a14) is selected from the group consisting of a lower alkyl group, a carbonyl group and a lower alkylcarbonyl group. One or two of the substituents may be substituted, and one of the groups described in the above (a2), (a15), (a16), (a17), (a18), (a30) and (a35) The aryl group constituting the part is halogen, hydroxyl group, lower alkyl group, lower alkoxy group, halogeno lower alkoxy group, aryl group, aryloxy group, methylenedioxy group, dihalogenomethylenedioxy group, carboxyl group, lower alkoxycarbonyl Group, a lower alkylcarbonyloxy group, a nitro group, a lower alkylamino group, a lower alkylcarbonylamino group, and an aminosulfonyl group, may be substituted with 1 to 3 substituents selected from the group (a5) , (A The heteroaryl group constituting a part of each group described in 19) to (a24) and (a31) is halogen, hydroxyl group, lower alkyl group, hydroxy lower alkyl group, halogeno lower alkyl group, aryl group, halogenoaryl group And may be substituted with 1 to 3 substituents selected from the group consisting of a lower alkylsulfanyl group, an aminocarbonyl group and a carboxyl group. Further, the saturated heterocyclic ring constituting a part of each group described in the above (a33) to (a38) is a 5- to 7-membered nitrogen-containing saturated heterocyclic group, and the group includes 1 to 2 The benzene ring may be condensed, and the group may have one lower alkyl group or lower alkylcarbonyl group on the nitrogen atom constituting the benzene ring, or on the carbon atom constituting the ring. May have 1 or 2 oxo groups.

Z ² : (b1) hydrogen atom, (b2) lower alkoxycarbonyl group, (b3) amino lower alkylcarbonyl group, (b4) lower alkenylcarbonyl group, (b5) lower alkylcarbonyl group having a saturated heterocyclic ring, (b6) A piperidino lower alkylcarbonyl group having a saturated heterocyclic ring, (b7) a carbonyl group having a saturated heterocyclic ring, and (b8) a lower alkylsulfonyl group.

  The amino group constituting a part of each group described in the above (b3) may be substituted with 1 or 2 lower alkyl groups. Further, the saturated heterocyclic ring constituting a part of each group described in the above (b5) to (b7) is a 5- to 7-membered nitrogen-containing saturated heterocyclic group and on the nitrogen atom constituting the ring. It may have one lower alkyl group.

Z ³ : (c1) hydroxyl group, (c2) lower alkoxy group, (c3) amino group, (c4) amino lower alkylamino group, (c5) piperazino group, (c6) amino lower alkyl piperazino group, (c7) Aminocarbonyl lower alkyl piperazino group, (c8) 1,4-diazepan-1-yl group, (c9) amino lower alkyl-1,4-diazepan-1-yl group, (c10) piperidino group, (c11) An aminopiperidino group, (c12) an amino lower alkylaminopiperidino group, (c13) an amino lower alkylpiperidino group, (c14) a pyrrolidino group, (c15) an amino group having a saturated heterocyclic ring, and (c16) a saturated heterocyclic ring. (C17) a piperazino group having a saturated heterocyclic ring, (c18) a lower alkyl piperazino group having a saturated heterocyclic ring, (c19) a carbonyl lower alkyl piperazino group having a saturated heterocyclic ring, (c20 ) A lower alkyl-1,4-diazepan-1-yl group having a saturated heterocyclic ring, (c21) a saturated heterocyclic ring A piperidino group having (c22) a lower alkylmorpholino group having a saturated heterocyclic ring.

Incidentally, the amino group of the above (c3), and each of (c4), (c6), (c7), (c9), (c11), (c12), (c13), (c15) and (c16) The amino group constituting a part of the group is a lower alkyl group, a hydroxy lower alkyl group, an aryl group, a heteroaryl group, an aryl lower alkyl group, an alkyloxyaryl lower alkyl group, a heteroaryl lower alkyl group and a lower alkoxycarbonyl group. The amino group constituting a part of the group described in the above (c11) may be substituted with one aryl lower alkylcarbonyl group, which may be substituted with 1 or 2 substituents selected from the group consisting of It may be. In addition, the piperazino group of (c5) and the 1,4-diazepan-1-yl group of (c8) have a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group, a lower alkyl aryl at the 4-position. Group, hydroxyaryl group, cyanoaryl group, halogenoaryl group, aryl lower alkyl group, lower alkoxyaryl lower alkyl group, halogenoaryloxy lower alkyl group, heteroaryl group, lower alkyl heteroaryl group, halogeno lower alkyl heteroaryl group, It may have any one of substituents selected from the group consisting of a cyanoheteroaryl group, a heteroaryl lower alkyl group, a lower alkoxycarbonyl group, and a lower alkylcarbonyl group. Furthermore, the saturated heterocyclic ring constituting a part of each group described in the above (c15) to (c22) is a 5- to 7-membered nitrogen-containing saturated heterocyclic group, and the group includes 1 to 2 The benzene ring may be condensed, and the group comprises a lower alkyl group, an aryl group, a cyanoaryl group, a lower alkylcarbonyl group, a halogeno lower alkylaryl group and an aryl lower alkyl group on the nitrogen atom constituting the benzene ring. It may have any one of substituents selected from the group. Furthermore, the piperazino group of (c5), the piperidino group of (c10) and the saturated heterocyclic ring constituting a part of each group described in (c15) to (c22) are on the carbon atoms constituting these rings. It may have any one of substituents selected from the group consisting of a hydroxyl group, an oxo group, a lower alkyl group, a hydroxy lower alkyl group, an aryl group, an aryl lower alkyl group, an aminocarbonyl group, and a lower alkylamino group. . ]
A 4-amino-5-cyanopyrimidine derivative represented by the formula or a pharmaceutically acceptable salt thereof.

Item 2. The 4-amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof according to Item 1, wherein R ² is a methylene group and R ³ is a hydrogen atom or a lower alkyl group.

Item 3. The 4-amino-5-cyanopyrimidine derivative according to Item 1, wherein R ¹ is a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (3) or a group (6). Or a pharmaceutically acceptable salt thereof.

Item 4. R ³ is a lower alkylene group, and Z ¹ is any group selected from (a2), (a14), (a15), (a28), (a32) and (a37) Or a pharmaceutically acceptable salt thereof.

Item 5. R ¹ is a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (4), a group (5) or a group (7) (wherein Z ¹ is a lower alkoxycarbonyl group or Item 4. A 4-amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof according to Item 1, which represents a hydrogen atom.

Item 6. The 4-amino-5-cyanopyrimidine derivative or the pharmaceutical formulation thereof according to Item 1, wherein R ¹ is a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is group (8). Acceptable salt.

Item 7. The item 4 according to item ¹ , wherein R ¹ is a hydrogen atom or a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (9), a group (10), or a group (11). -Amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof.

Item 8. R ¹ is a hydrogen atom or a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (9), a group (10) or a group (11) (provided that Z ³ is (c1 ), (C2), (c4), (c5), (c6), (c7), (c8), (c10), (c11), (c15), (c16), (c18), (c21) or The 4-amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof according to Item 1, which is (showing (c22)).

Item 9. R ¹ is an acetyl group, R ² is a methylene group, and R ³ is a group (9) (where Z ³ is (c4), (c5), (c6), (c10), ( The 4-amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof according to Item 1, which is c11), (c16), (c18), (c21) or (c22).

Item 10. The 4-amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of Items 1-9 selected from 1) to 19) below:
1) N- {4- [6-amino-5-cyano-2- (pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
2) N- {4- [6-Amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
3) N- {4- [6-Amino-5-cyano-2- (6- {4- [2- (4-methylpiperazin-1-yl) acetyl] piperazin-1-ylmethyl} pyridin-2-yl Methylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
4) N- [4- (6-Amino-5-cyano-2- {6- [3- (4-methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidine- 4-yl) phenyl] acetamide,
5) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl) propion Amide,
6) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl)- N-methylpropionamide,
7) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminopropyl)- N-methylpropionamide,
8) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-methylpiperidine-1- Ylethyl) propionamide,
9) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-diethylaminoethyl) propionamide ,
10) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N-methyl-N- (1-methyl Piperidin-4-yl) propionamide,
11) N- (4- {6-amino-2- [6- (3- [1,4 '] bipiperidinyl-1'-yl-3-oxopropyl) pyridin-2-ylmethylsulfanyl] -5-cyano Pyrimidin-4-yl} phenyl) acetamide,
12) N- [4- (6-Amino-5-cyano-2- {6- [3-oxo-3- (2-piperidin-1-ylmethylmorpholin-4-yl) propyl] pyridin-2-yl Methylsulfanyl} pyrimidin-4-yl) phenyl] acetamide,
13) N- {4- [6-Amino-5-cyano-2- (6- {3- [2- (4-ethylpiperazin-1-ylmethyl) morpholin-4-yl] -3-oxopropyl} pyridine -2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
14) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-diethylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-yl Methylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
15) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-diisopropylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridine-2- Ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
16) N- {4- [6-Amino-5-cyano-2- (6- {3-oxo-3- [4- (2-pyrrolidin-1-ylethyl) piperazin-1-yl] propyl} pyridine- 2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
17) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-morpholin-4-ylethyl) piperazin-1-yl] -3-oxopropyl} pyridine- 2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
18) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-diethylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-yl Methylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,
19) N- [4- (6-Amino-5-cyano-2- {6- [3- (4-methyl- [1,4] diazepan-1-yl) -3-oxopropyl] pyridine-2- Ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide.

  The 4-amino-5-cyanopyrimidine derivative of the present invention has a pyrimidine skeleton, a phenyl ring having a specific substituent is substituted at the 6-position of the pyrimidine ring, and a sulfanylalkylene chain at the 2-position of the pyrimidine ring. The pyridine ring is substituted, or further has a specific feature on the pyridine ring. Based on this characteristic structure, the compound of the present invention has a pharmacological feature that it excels in the action of activating the adenosine A2a receptor, that is, the action of adenosine A2a receptor. Conventionally, a compound having such a unique structural feature has not been known, and it is also a matter that cannot be predicted from the prior art that a compound having such a structural feature can exert some pharmacological action. The compound of the present invention is useful not only as an adenosine A2a receptor agonist, but also as an intraocular pressure-lowering drug, a glaucoma therapeutic drug, etc. based on the above-mentioned adenosine A2a receptor agonistic action.

Compound of the Present Invention The term “lower alkyl group” used for each group containing carbon in the present specification means a linear or branched alkyl group having 1 to 6 carbon atoms, ie, C _1-6 .

  The terms “lower alkoxy group” and “lower alkylene group” also mean straight or branched alkoxy groups and alkylene groups having 1 to 6 carbon atoms.

The “lower alkenyl group”, “lower alkenylene group” and “lower alkynylene group” are each a straight or branched alkenyl group, alkenylene group and alkynylene group having 2 to 6 carbon atoms (C _2-6 ). means.

  The “aryl group” means a monovalent group composed of a monocyclic or polycyclic aromatic hydrocarbon. Specific examples include a phenyl group and a naphthyl group.

  The “heteroaryl group” is a 5- to 6-membered monocyclic aromatic heterocycle having 1 or more, particularly 1 to 3 of the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or the group Means a monovalent group consisting of an aromatic heterocyclic group condensed with an aryl group. Specific examples include furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, benzofuryl, indolyl, benzothiazolyl, pyridyl, pyrazyl group and the like.

  “Saturated heterocycle” means a 5- to 7-membered saturated heterocycle having one or more, particularly 1 to 3, the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The saturated heterocyclic ring is, in each group having this, specifically pyrrolidyl, pyrrolidino, piperidyl, piperidino, piperazyl, piperazino, 1,4-diazepan-1-yl, tetrahydrofuryl, 1,3-dioxolanyl, tetrahydro Included as monovalent saturated heterocyclic groups such as thienyl, morpholyl, morpholino and tetrahydroimidazolyl groups. That is, for example, taking a lower alkyl group having a saturated heterocyclic ring as an example, the lower alkyl group means a lower alkyl group substituted by the saturated heterocyclic group. The bonding mode of the saturated heterocyclic group in the lower alkyl group substituted with the saturated heterocyclic ring is not particularly limited, and is bonded to the lower alkyl group at a nitrogen atom as a hetero atom constituting the heterocyclic group. Alternatively, it may be bonded to a lower alkyl group at a carbon atom. The 5- to 7-membered saturated heterocyclic group may be further condensed with 1 to 2 benzene rings. Examples of such fused ring groups include dihydroindolyl, dihydroisoindolyl, tetrahydroquinolyl, tetrahydroquinolino, benzomorpholyl, benzomorpholino groups and the like.

  Hereinafter, each group representing the compound of the present invention represented by the general formula (1) will be specifically described. These groups are not limited to the compound represented by the general formula (1), and the same applies to the case where each compound represented by another general formula described in the present specification is shown.

Specific examples of the lower alkylcarbonyl group represented by R ¹ include acetyl, propanoyl, butanoyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl, isopropylcarbonyl group, etc. Among them, acetyl and propanoyl groups are preferable. .

Specific examples of the lower alkenylcarbonyl group represented by R ¹ include acryloyl, methacryloyl, crotonoyl, and isocrotonoyl groups. Of these, acryloyl group is preferred.

Specific examples of the lower alkoxycarbonyl group represented by R ¹ include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, n-butoxycarbonyl group and the like, and among these, methoxycarbonyl group is preferable.

Specific examples of the lower alkylene group represented by R ² include structural isomers such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene or hexamethylene and 1-methylethylene. Of these, a methylene group is preferred.

Specific examples of the lower alkyl group represented by R ³ include structural isomers such as methyl, ethyl, propyl, butyl, pentyl or hexyl and isopropyl. Of these, a methyl group is preferred.

Specific examples of the lower alkylene group represented by R ⁴ include structural isomers such as methylene, ethylene, trimethylene, tetramethylene, heptamethylene, hexamethylene and 1-methylethylene. Of these, when R ³ is a group (3), the lower alkylene group represented by R ⁴ is preferably a methylene group or an ethylene group, and when the R ³ group is a group (6) or a group (8), The lower alkylene group represented by R ⁴ is preferably a methylene group. When the R ³ group is the group (9), the lower alkylene group represented by R ⁴ is preferably an ethylene group or a tetramethylene group.

Specific examples of the lower alkyl group represented by R ⁵ include these structural isomers such as methyl, ethyl, propyl, butyl, pentyl or hexyl and isopropyl. Of these, a methyl group is preferred.

Specific examples of the lower alkenylene group represented by R ⁶ include linear lower alkenylene groups such as ethenylene, propenylene, butenylene, pentenylene, hexenylene, butanedienylene or structural isomers such as 2-methylpropenylene group. it can. Of these, ethenylene groups are preferred.

Specific examples of the lower alkynylene group represented by R ⁷ include linear alkynylene groups such as ethynylene, propynylene, butynylene, pentynylene, hexynylene, butanediinylene, and structural isomers such as 3-methylbutynylene group. Of these, a butynylene group is preferred.

Specific examples of the lower alkyl group represented by R ⁸ include these structural isomers such as methyl, ethyl, propyl, butyl, pentyl or hexyl and isopropyl. Of these, an ethyl group is preferred.

Specific examples of the lower alkyl group (a1) represented by Z ¹ include linear lower alkyl groups such as methyl, ethyl, propyl, butyl, pentyl and hexyl, and structural isomers such as isopropyl. Of these, C _1-4 alkyl groups are preferred.

The aryl lower alkyl group (a2) represented by Z ¹ means a lower alkyl group substituted with an aryl group. Specific examples include benzyl, phenethyl, phenylpropyl, naphthylmethyl groups, and the like. Of these, a benzyl group or a phenethyl group is preferred.

The aminoaryl lower alkyl group (a3) represented by Z ¹ means an aryl lower alkyl group having an amino group on the aryl group. Specific examples include aminobenzyl, aminophenethyl, aminophenylpropyl, and aminonaphthylmethyl groups. Of these, an aminobenzyl group or an aminophenethyl group is preferable.

The aryl lower alkenyl group (a4) represented by Z ¹ means a lower alkenyl group substituted with an aryl group. Specific examples include phenylethenyl, phenylpropenyl, and phenylbutenyl groups. Of these, a phenylpropenyl group is preferred.

The heteroaryl lower alkyl group (a5) represented by Z ¹ means a lower alkyl group substituted with a heteroaryl group. Specific examples include furylmethyl, pyrazolylethyl, imidazolylpropyl, and pyridylmethyl groups. Of these, a furylmethyl group or a pyridylmethyl group is preferable.

The heteroaryl lower alkenyl group (a6) represented by Z ¹ means a lower alkenyl group substituted with a heteroaryl group. Specific examples include pyridylethenyl, pyridylpropenyl, furylpropenyl group and the like. Of these, a pyridylpropenyl group or a furylpropenyl group is preferable.

The heteroarylaryl lower alkyl group (a7) represented by Z ¹ means an aryl lower alkyl group in which a heteroaryl group is substituted on the aryl group. Specific examples include furylphenylmethyl, thienylphenylethyl, pyridylphenylpropyl, triazolylphenylmethyl, imidazolylphenylmethyl groups, and the like. Of these, a triazolylphenylmethyl group or an imidazolylphenylmethyl group is preferable.

Examples of the hydroxy lower alkyl group (a8) represented by Z ¹ include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, and 4-hydroxybutyl groups. Of these, 3-hydroxypropyl and 4-hydroxybutyl groups are preferred.

Examples of the aryloxy lower alkyl group (a9) represented by Z ¹ include phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 1-phenoxypropyl, 2-phenoxypropyl, and 3-phenoxypropyl groups. Of these, a 3-phenoxypropyl group is preferred.

Examples of the amino lower alkyl group (a10) represented by Z ¹ include aminomethyl, 1-aminoethyl, 2-aminoethyl, 1-aminopropyl, 2-aminopropyl, and 3-aminopropyl groups. Of these, 2-aminoethyl and 3-aminopropyl groups are preferred.

The aminocarbonyl lower alkyl group (a11) represented by Z ¹ includes aminocarbonylmethyl, 1-aminocarbonylethyl, 2-aminocarbonylethyl, 1-aminocarbonylpropyl, 2-aminocarbonylpropyl, 3-aminocarbonylpropyl group. Among them, an aminocarbonylmethyl group is preferable.

Examples of the lower alkylcarbonyl group (a12) represented by Z ¹ include acetyl, propanoyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl, isopropylcarbonyl group and the like. Among these, acetyl and propanoyl groups are exemplified. preferable.

Examples of the lower alkoxy lower alkylcarbonyl group (a13) represented by Z ¹ include methoxymethylcarbonyl, methoxyethylcarbonyl, ethoxyethylcarbonyl group and the like, and among these, methoxymethylcarbonyl group is preferable.

Examples of amino lower alkylcarbonyl groups represented by Z ¹ and Z ² ((a14) and (b3)) include aminomethylcarbonyl, aminoethylcarbonyl, aminopropylcarbonyl, aminobutylcarbonyl groups, etc. Aminomethylcarbonyl and aminoethylcarbonyl groups are preferred.

Examples of the arylcarbonyl group (a15) represented by Z ¹ include benzoyl and naphthylcarbonyl groups, and among these, a benzoyl group is preferable.

Examples of the aryl lower alkylcarbonyl group (a16) represented by Z ¹ include benzylcarbonyl, naphthylmethylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, phenylbutylcarbonyl group and the like. Among these, benzylcarbonyl and phenethylcarbonyl groups are exemplified. preferable.

Examples of the aryl lower alkenylcarbonyl group (a17) represented by Z ¹ include a phenylethenylcarbonyl group, a phenylpropenylcarbonyl group, a phenylbutenylcarbonyl group, and the like. Among these, a phenylethenylcarbonyl group is preferable.

Examples of the aryloxy lower alkylcarbonyl group (a18) represented by Z ¹ include phenoxymethylcarbonyl, phenoxyethylcarbonyl, phenoxypropylcarbonyl, phenoxybutylcarbonyl group and the like, and among these, phenoxymethylcarbonyl and phenoxyethylcarbonyl groups Is preferred.

Examples of the heteroarylcarbonyl group (a19) represented by Z ¹ include furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, thiazolylcarbonyl, pyridylcarbonyl, quinolylcarbonyl group and the like. Among these, pyridylcarbonyl group, furyl A carbonyl group and a thienylcarbonyl group are preferred.

Examples of the heteroaryl lower alkylcarbonyl group (a20) represented by Z ¹ include furylmethylcarbonyl, furylethylcarbonyl, thienylmethylcarbonyl, pyridylmethylcarbonyl, pyridylethylcarbonyl, pyridylpropylcarbonyl group, etc. Thienylmethylcarbonyl and pyridylmethylcarbonyl groups are preferred.

Examples of the heteroaryl lower alkenylcarbonyl group (a21) represented by Z ¹ include a pyridylacryloyl group and an imidazolylacryloyl group. Among these, a pyridylacryloyl group is preferable.

Examples of the heteroaryloxy lower alkylcarbonyl group represented by Z ¹ (a22) include pyridyloxymethylcarbonyl, quinolyloxyethylcarbonyl, tetrahydroquinolinyloxymethylcarbonyl, tetrahydroquinolinyloxypropylcarbonyl groups and the like, Of these, tetrahydroquinolinyloxymethylcarbonyl and tetrahydroquinolinyloxypropylcarbonyl groups are preferred.

Examples of the heteroarylsulfanyl lower alkylcarbonyl group (a23) represented by Z ¹ include furylsulfanylmethylcarbonyl, pyridylsulfanylethylcarbonyl, quinolylsulfanylpropylcarbonyl group, etc. Among them, pyridylsulfanylmethylcarbonyl group is preferred. .

Examples of the heteroarylarylcarbonyl group (a24) represented by Z ¹ include pyrrolylphenylcarbonyl, pyrazolylphenylcarbonyl, imidazolylphenylcarbonyl, triazolylphenylcarbonyl, thienylphenylcarbonyl, furylphenylcarbonyl, pyridylphenylcarbonyl group, etc. Of these, pyrrolylphenylcarbonyl, pyrazolylphenylcarbonyl, imidazolylphenylcarbonyl, and triazolylphenylcarbonyl groups are preferred.

Examples of the arylsulfanyl lower alkylcarbonyl group (a25) represented by Z ¹ include phenylsulfanylmethylcarbonyl, phenylsulfanylethylcarbonyl, phenylsulfanylpropylcarbonyl group and the like, and among them, phenylsulfanylmethylcarbonyl group is preferable.

Examples of the arylcarbonyl lower alkylcarbonyl group (a26) represented by Z ¹ include benzoylmethylcarbonyl, benzoylethylcarbonyl, benzoylpropylcarbonyl group and the like, and among these, benzoylethylcarbonyl group is preferable.

Examples of the arylamino lower alkylcarbonyl group (a27) represented by Z ¹ include phenylaminomethylcarbonyl, phenylaminoethylcarbonyl, phenylaminopropylcarbonyl group and the like, and among these, phenylaminomethylcarbonyl group is preferable.

Examples of the lower alkoxycarbonyl group represented by Z ¹ and Z ² ((a28) and (b2)) include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, isopropoxycarbonyl group and the like. It can be illustrated. Of these, methoxycarbonyl and t-butoxycarbonyl groups are preferred.

Examples of lower alkylsulfonyl groups represented by Z ¹ and Z ² ((a29) and (b8)) include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl groups and the like. In particular, the lower alkylsulfonyl group (a29) represented by Z ¹ is preferably a methylsulfonyl or ethylsulfonyl group, and the lower alkylsulfonyl group (b8) represented by Z ² is an ethylsulfonyl or propylsulfonyl group. Is preferred.

Examples of the arylsulfonyl group (a30) represented by Z ¹ include phenylsulfonyl, toluenesulfonyl, naphthalenesulfonyl group and the like, and among these, phenylsulfonyl group is preferable.

Examples of the heteroarylsulfonyl group (a31) represented by Z ¹ include a furylsulfonyl group, a thienylsulfonyl group, a pyridylsulfonyl group, an imidazolylsulfonyl group, and the like. Among these, an imidazolylsulfonyl group is preferable.

The lower alkyl group (a33) having a saturated heterocyclic ring represented by Z ¹ means a lower alkyl group substituted with a saturated heterocyclic group. Specific examples include pyrrolidinoethyl, piperidinoethyl, piperidylethyl, morpholinoethyl, morpholylmethyl groups and the like, and among these, piperidinoethyl and morpholinoethyl groups are preferred.

The carbonyl lower alkyl group (a34) having a saturated heterocyclic ring represented by Z ¹ means a carbonyl lower alkyl group substituted with a saturated heterocyclic group. Specific examples include pyrrolidinocarbonylethyl, piperidinocarbonylethyl, piperidylcarbonylethyl, morpholinocarbonylethyl, morpholylcarbonylmethyl group and the like, and among these, piperidinocarbonylmethyl group is preferable.

The aryl lower alkyl group (a35) having a saturated heterocyclic ring represented by Z ¹ means an aryl lower alkyl group having a saturated heterocyclic group on the aryl ring. Specific examples include pyrrolidinophenylethyl, piperidinophenylmethyl, piperidylphenylethyl, morpholinophenylethyl, morpholylphenylmethyl, piperazinophenylmethyl groups, etc. Among these, piperazinophenylmethyl Groups are preferred.

A carbonyl group having a saturated heterocyclic ring represented by Z ¹ and Z ² ((a36) and (b7)) is specifically pyrrolidinocarbonyl, piperidinocarbonyl, piperidylcarbonyl, morpholinocarbonyl, morpholylcarbonyl , Piperazinocarbonyl, piperazylcarbonyl, thiazolylcarbonyl, pyrrolylcarbonyl and the like, among which piperazinocarbonyl, thiazolylcarbonyl and pyrrolylcarbonyl are preferred.

Specific examples of the lower alkylcarbonyl group having a saturated heterocyclic ring represented by Z ¹ and Z ² ((a37) and (b5)) include pyrrolidinoethylcarbonyl, piperidinomethylcarbonyl, piperidinoethylcarbonyl, Examples include piperidylmethylcarbonyl, morpholinoethylcarbonyl, morpholylmethylcarbonyl, piperazinomethylcarbonyl, piperazylpropylcarbonyl, thiazolylmethylcarbonyl, etc. Among these, piperazinomethylcarbonyl, piperidinomethyl Carbonyl and piperidinoethylcarbonyl groups are preferred.

Specific examples of the arylcarbonyl group (a38) having a saturated heterocyclic ring represented by Z ¹ include pyrrolidinophenylcarbonyl, piperidinophenylcarbonyl, piperidylphenylcarbonyl, morpholinophenylcarbonyl, morpholylphenylcarbonyl, thiomorpholino Examples thereof include phenylcarbonyl, piperazinophenylcarbonyl group, etc. Among them, pyrrolidinophenylcarbonyl, morpholylphenylcarbonyl and thiomorpholinophenylcarbonyl groups are preferable.

Specific examples of the substituent that the group constituting a part of each group represented by Z ¹ may have include the following groups.

  That is, specific examples of the lower alkyl group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, and isobutyl groups. Of these, methyl, ethyl and isopropyl groups are preferred.

  Specific examples of the lower alkylcarbonyl group include acetyl, propanoyl, butanoyl, butylcarbonyl, pentylcarbonyl group and the like, and among these, acetyl group is preferable.

  Specific examples of halogen include fluorine, chlorine, bromine and iodine atoms, and among these, fluorine and chlorine atoms are preferred.

Specific examples of the lower alkoxy group include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy and isopropoxy. Of these, C _1-4 alkoxy groups are preferred.

  Specific examples of the halogeno lower alkoxy group include chloromethoxy, dichloromethoxy, trichloromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy group, and the like, among which trifluoromethoxy group is preferable.

  Specific examples of the aryl group include phenyl and naphthyl groups, and among these, a phenyl group is preferable.

  Specific examples of the aryloxy group include a phenoxy group and a naphthoxy group. Among these, a phenoxy group is preferable.

  Specific examples of the dihalogenomethylenedioxy group include difluoromethylenedioxy and dichloromethylenedioxy groups, and a difluoromethylenedioxy group is preferred.

  Specific examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl group and the like, and methoxycarbonyl group is preferable.

  Specific examples of the lower alkylcarbonyloxy group include an acetoxy group and a propylcarbonyloxy group. Among these, an acetoxy group is preferable.

  Specific examples of the lower alkylamino group include a mono- or di (lower alkyl) amino group such as methylamino, dimethylamino, diethylamino, diisopropylamino group, etc. Among them, dimethylamino group is preferable.

  Specific examples of the lower alkylcarbonylamino group include acetylamino and propionylamino groups. Of these, acetylamino group is preferred.

  Specific examples of the hydroxy lower alkyl group include hydroxyl such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylethyl group, etc. A lower alkyl group having one group can be exemplified, and among these, a hydroxymethyl group or a 2-hydroxyethyl group is preferable.

  Specific examples of the halogeno lower alkyl group include lower alkyl groups having 1 to 5 halogen atoms such as chloroethyl, dichloromethyl, trifluoromethyl, and pentafluoroethyl groups. Among these, trifluoromethyl groups are preferred. .

  Specific examples of the halogenoaryl group include chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl, pentafluorophenyl, bromophenyl, iodophenyl, chloronaphthyl group, etc. Among them, chlorophenyl group is preferable.

  Specific examples of the lower alkylsulfanyl group include a methylsulfanyl, ethylsulfanyl, propylsulfanyl group, and the like. Among these, a methylsulfanyl group is preferable.

  Aminoaryl lower alkyl group (a3), amino lower alkyl group (a10), aminocarbonyl lower alkyl group (a11), and amino group constituting a part of amino lower alkylcarbonyl group (a14) are one or two lower alkyl groups Specific examples of the group substituted with a group include dimethylaminophenylethyl, dimethylaminoethyl, diethylaminoethyl, diisopropylaminoethyl, dimethylaminocarbonylmethyl, diethylaminomethylcarbonyl, and diethylaminoethylcarbonyl groups. Specific examples of the group in which the amino group is substituted with one carbonyl group include N-formylaminomethylcarbonyl group, and the amino group is substituted with one lower alkylcarbonyl group. As a specific example, an acetylaminomethylcarbonyl group can be exemplified.

  Aryl lower alkyl group (a2), arylcarbonyl group (a15), aryl lower alkylcarbonyl group (a16), aryl lower alkenylcarbonyl group (a17), aryloxy lower alkylcarbonyl group (a18), arylsulfonyl group (a30) and Specific examples of the group in which the aryl group constituting a part of each group of the aryl lower alkyl group (a35) having a saturated heterocyclic ring is substituted with a halogen atom include chlorophenylcarbonyl, dichloro (aminosulfonyl) phenylcarbonyl, chlorophenyl Examples include methylcarbonyl and fluoro (4-methylpiperazino) phenylmethyl groups. Specific examples of the group in which the aryl group is substituted with a hydroxyl group include a hydroxyphenylmethyl group. Specific examples of the group in which the aryl group is substituted with a lower alkyl group include methylphenylcarbonyl, methylphenylmethylcarbonyl, methylphenoxymethylcarbonyl, and methylphenylsulfonyl groups. Specific examples of the group in which the aryl group is substituted with a lower alkoxy group include methoxyphenylmethyl, trimethoxyphenylmethyl, butoxyphenylmethyl, ethoxyphenylmethyl, methoxyphenylcarbonyl, methoxyphenylmethylcarbonyl, methoxyphenoxymethylcarbonyl, A methoxyphenylsulfonyl group can be illustrated. Specific examples of the group in which the aryl group is substituted with a halogeno lower alkoxy group include a trifluoromethoxyphenylmethylcarbonyl group. Specific examples of the group in which the aryl group is substituted with an aryl group include a biphenyl group. Specific examples of the group in which the aryl group is substituted with an aryloxy group include phenoxyphenylmethyl and phenoxyphenylcarbonyl groups. Specific examples of the group in which the aryl group is substituted with a methylenedioxy group include methylenedioxyphenylmethyl and methylenedioxyphenylcarbonyl groups. Specific examples of the group in which the aryl group is substituted with a dihalogenomethylenedioxy group include a difluoromethylenedioxyphenylmethyl group. Specific examples of the group in which the aryl group is substituted with a carboxyl group include a hydroxycarbonylphenylmethyl group. Specific examples of the group in which the aryl group is substituted with a lower alkoxycarbonyl group include methoxycarbonylphenylmethyl and methoxycarbonylphenylcarbonyl groups. Specific examples of the group in which the aryl group is substituted with a lower alkylcarbonyloxy group include acetoxyphenylmethyl and acetoxyphenylcarbonyl groups. Specific examples of the group in which the aryl group is substituted with a nitro group include a nitrophenylcarbonyl group. Specific examples of the group in which the aryl group is substituted with a lower alkylamino group include dimethylaminophenylcarbonyl and dimethylaminophenylethenylcarbonyl groups. Specific examples of the group in which the aryl group is substituted with a lower alkylcarbonylamino group include an acetylaminophenylcarbonyl group. Specific examples of the group in which the aryl group is substituted with an aminosulfonyl group include a dichloro (aminosulfonyl) phenylcarbonyl group.

  Heteroaryl lower alkyl group (a5), heteroarylcarbonyl group (a19), heteroaryl lower alkylcarbonyl group (a20), heteroaryl lower alkenylcarbonyl group (a21), heteroaryloxy lower alkenylcarbonyl group (a22), heteroaryl Specific examples of the group in which the heteroaryl group constituting a part of each group described in the sulfanyl lower alkylcarbonyl group (a23), heteroarylarylcarbonyl group (a24) and heteroarylsulfonyl group (a31) is substituted with halogen Examples thereof include chlorothienylmethyl, dichloroimidazolylmethyl, and chloro (hydroxy) pyridylcarbonyl groups. Specific examples of the group in which the heteroaryl group is substituted with a hydroxyl group include hydroxypyridylcarbonyl and chloro (hydroxy) pyridylcarbonyl groups. Specific examples of the group in which the heteroaryl group is substituted with a lower alkyl group include a methylthiazolylmethyl, n-hexyltetrazolylmethyl, methylisoxazolylmethyl, and methylimidazolylmethyl group. Specific examples of the group in which the heteroaryl group is substituted with a hydroxy lower alkyl group include a hydroxymethylpyridylmethyl group. Specific examples of the group in which the heteroaryl group is substituted with a halogeno lower alkyl group include a trifluoromethylbenzofuranylmethyl group. Specific examples of the group in which the heteroaryl group is substituted with an aryl group include phenylthiazolylmethyl and phenylimidazolylmethyl groups. Specific examples of the group in which the heteroaryl group is substituted with a halogenoaryl group include a chlorophenylpyrrolylmethyl group. Specific examples of the group in which the heteroaryl group is substituted with a lower alkylsulfanyl group include a methylsulfanylpyridylcarbonyl group. Specific examples of the group in which the heteroaryl group is substituted with an aminocarbonyl group include an aminocarbonylpyrazolylcarbonyl group. Specific examples of the group in which the heteroaryl group is substituted with a carboxyl group include a hydroxycarbonylfurylmethyl group and a hydroxycarbonylthienylmethyl group.

  The saturated heterocyclic ring constituting a part of each group described in (a33) to (a38) has a specific substituent (lower alkyl group or lower substituent as a substituent on the nitrogen atom) on the constituent nitrogen atom or carbon atom. An alkoxycarbonyl group, and an oxo group as a substituent on the carbon atom). Among these groups, preferred groups are exemplified by the following groups.

  That is, in the case of the lower alkyl group (a33) having a saturated heterocyclic ring, and the group having one lower alkyl group on the nitrogen atom constituting the heterocyclic ring,

Etc. can be illustrated. In this group, Me means a methyl group (the same applies hereinafter).

  In the case of the aryl lower alkyl group (a35) having a saturated heterocyclic ring, and the group having one lower alkyl group on the nitrogen atom constituting the heterocyclic ring,

Etc. can be illustrated.

  In the case of the carbonyl group (a36) having a saturated heterocyclic ring, and the group having one lower alkylcarbonyl group on the nitrogen atom constituting the heterocyclic ring,

Etc. can be illustrated. In the above groups, Ac means an acetyl group (hereinafter the same).

  In the case of the carbonyl group (a36) having a saturated heterocyclic ring, and a group having one oxo group on the carbon atom constituting the heterocyclic ring,

Etc. can be illustrated.

  In the case of the lower alkylcarbonyl group (a37) having a saturated heterocyclic ring, and the group having one lower alkyl group on the nitrogen atom constituting the heterocyclic ring,

Etc. can be illustrated.

  In the case of the lower alkylcarbonyl group (a37) having a saturated heterocyclic ring and further having two oxo groups on the carbon atom constituting the heterocyclic ring,

Etc. can be illustrated.

  In the case of the arylcarbonyl group (a38) having a saturated heterocyclic ring, and the group having one oxo group on the carbon atom constituting the heterocyclic ring,

Etc. can be illustrated.

Among the groups described in (b1) to (b8) represented by Z ² , (b2), (b3), (b5), (b7) and (b8) are as described above.

Specific examples of the lower alkenylcarbonyl group (b4) represented by Z ² include acryloyl, methacryloyl, crotonoyl, and isocrotonoyl groups. Among these, acryloyl group is preferable.

Specific examples of the piperidino lower alkylcarbonyl group (b6) having a saturated heterocyclic ring represented by Z ² include pyrrolidinopiperidinomethylcarbonyl, pyrrolidylpiperidinoethylcarbonyl, piperidinopiperidinomethylcarbonyl, piperidyl Examples include piperidinoethylcarbonyl, morpholinopiperidinoethylcarbonyl, piperazinopiperidinopropylcarbonyl groups and the like. As the group, preferably,

Etc. can be illustrated.

Specific examples of the lower alkyl group as a substituent that the amino group constituting a part of the group described in (b3) represented by Z ² may have include methyl, ethyl, propyl, butyl, pentyl, Mention may be made of these structural isomers such as hexyl and isopropyl. Of these, methyl, ethyl and isopropyl groups are preferred. The lower alkyl group that can be substituted on the nitrogen atom of the saturated heterocyclic group constituting a part of each group of (b5) to (b7) is the same as above. Examples of each group having an amino group having a lower alkyl group and a saturated heterocyclic ring having a lower alkyl group on the nitrogen atom preferably include dimethylaminomethylcarbonyl and 4-methylpiperazinocarbonyl groups. it can.

Examples of the lower alkoxy group (c2) represented by Z ³ include methoxy, ethoxy, t-butoxy, n-butoxy group and the like. Among these, methoxy, ethoxy and t-butoxy groups are preferable.

Examples of the amino lower alkylamino group (c4) represented by Z ³ include aminomethylamino, aminoethylamino, aminopropylamino, aminobutylamino group, etc., among which aminoethylamino and aminopropylamino groups are preferable.

Examples of the amino lower alkyl piperazino group (c6) represented by Z ³ include aminomethylpiperazino, aminoethylpiperazino, aminopropylpiperazino, aminobutylpiperazino group and the like. In these, aminoethylpiperazino and aminopropylpiperazino groups are preferred.

Examples of the aminocarbonyl lower alkyl piperazino group (c7) represented by Z ³ include aminocarbonylmethylpiperazino, aminocarbonylethylpiperazino, aminocarbonylpropylpiperazino, aminocarbonylbutylpiperazino group, etc. Of these, aminocarbonylmethylpiperazino group is preferred.

The amino lower alkyl-1,4-diazepan-1-yl group (c9) represented by Z ³ includes aminomethyl-1,4-diazepan-1-yl, aminoethyl-1,4-diazepan-1-yl , Aminopropyl-1,4-diazepan-1-yl, aminobutyl-1,4-diazepan-1-yl group, etc., among which aminopropyl-1,4-diazepan-1-yl group is preferable.

Examples of amino lower alkylaminopiperidino group (c12) represented by Z ³ include aminomethylaminopiperidino, aminoethylaminopiperidino, aminopropylaminopiperidino, aminobutylaminopiperidino group, etc. Of these, the aminoethylaminopiperidino group is preferred.

Examples of the amino lower alkyl piperidino group (c13) represented by Z ³ include aminomethyl piperidino, aminoethyl piperidino, aminopropyl piperidino, aminobutyl piperidino group, etc. In this case, an aminoethylpiperidino group is preferable.

Examples of the amino group (c15) having a saturated heterocyclic ring represented by Z ³ include piperidinoamino, piperidylamino, piperazinoamino, piperazylamino, pyrrolidylamino, morpholylamino group and the like, and among these, piperidinoamino and piperazinoamino groups are preferable.

Examples of the lower alkylamino group (c16) having a saturated heterocyclic ring represented by Z ³ include piperidinoethylamino, piperidylmethylamino, pyrrolidinoethylamino, morpholinopropylamino, piperazinopropylamino group, and the like. Of these, piperidinoethylamino group is preferred.

Examples of the piperazino group (c17) having a saturated heterocyclic ring represented by Z ³ include piperidyl piperazino and morpholyl piperazino groups. Among these, piperidyl piperazino groups are preferred.

The lower alkyl piperazino group (c18) having a saturated heterocyclic ring represented by Z ³ means a lower alkyl piperazino group in which a saturated heterocyclic group is substituted on the lower alkyl group. Specific examples include pyrrolidinoethylpiperazino, morpholinoethylpiperazino, piperidinoethylpiperazino, piperidylethylpiperazino, piperidylmethylpiperazino, 1,3-dioxolanylmethylpiperazino, tetrahydro Examples include a furylmethyl piperazino group, and among these, pyrrolidinoethylpiperazino, morpholinoethylpiperazino, piperidinoethylpiperazino, and piperidylmethylpiperazino groups are preferred.

Specific examples of the carbonyl lower alkylpiperazino group (c19) having a saturated heterocyclic ring represented by Z ³ include pyrrolidinocarbonylmethylpiperazino, piperidinocarbonylethylpiperazino group, etc., and pyrrolidino A carbonylmethyl piperazino group is preferred.

Specific examples of the lower alkyl-1,4-diazepan-1-yl group (c20) having a saturated heterocyclic ring represented by Z ³ include morpholinopropyl-1,4-diazepan-1-yl, piperidinoethyl-1,4 -A diazepan-1-yl group can be exemplified, and among these, a morpholinopropyl-1,4-diazepan-1-yl group is preferable.

Specific examples of the piperidino group (c21) having a saturated heterocycle represented by Z ³ is piperidinopiperidino, piperazino piperidinocarbonyl, morpholino piperidinocarbonyl, etc. can be exemplified morpholinocarbonyl Lupi piperidino group Of these, piperidinopiperidino and piperazinopiperidino groups are preferred.

Specific examples of the lower alkylmorpholino group (c22) having a saturated heterocyclic ring represented by Z ³ include piperidinomethylmorpholino, piperazinomethylmorpholino, 1,4-diazepan-1-ylmethylmorpholino group and the like. Piperidinomethylmorpholino and piperazinomethylmorpholino groups are preferred.

  Amino lower alkylamino group (c4), amino lower alkyl piperazino group (c6), aminocarbonyl lower alkyl piperazino group (c7), amino lower alkyl-1,4-diazepan-1-yl group (c9), Aminopiperidino group (c11), amino lower alkylaminopiperidino group (c12), amino lower alkylpiperidino group (c13), amino group having saturated heterocyclic ring (c15) and lower alkylamino group having saturated heterocyclic ring ( c16) an amino group constituting part of the amino group, and the amino group (c3) is a lower alkyl group, a hydroxy lower alkyl group, an aryl group, a heteroaryl group, an aryl lower alkyl group, an alkoxyaryl lower alkyl group, or a heteroaryl lower alkyl group. The group substituted with 1-2 substituents selected from the group consisting of a group, a lower alkylcarbonyl group and a lower alkoxycarbonyl group is preferably It can be exemplified each group.

  In each of the groups exemplified above, Ph represents a phenyl group, Boc represents a t-butoxycarbonyl group, i-Pr represents an isopropyl group, n-Pr represents an n-propyl group, and Et represents an ethyl group. (same as below).

  The group in which the amino group constituting a part of the aminopiperidino group (c11) is substituted with an aryl lower alkylcarbonyl group is preferably

Etc. can be illustrated.

  Piperazino group (c5) and 1,4-diazepan-1-yl group (c8) have a lower alkyl group, hydroxy lower alkyl group, lower alkoxy lower alkyl group, aryl group, lower alkyl aryl group, hydroxyl aryl at the 4-position Group, cyanoaryl group, halogenoaryl group, aryl lower alkyl group, lower alkoxyaryl lower alkyl group, halogenoaryloxy lower alkyl group, heteroaryl group, lower alkyl heteroaryl group, halogeno lower alkyl heteroaryl group, cyanoheteroaryl group Specific examples of the group having any one substituent selected from the group consisting of a heteroaryl lower alkyl group, a lower alkoxycarbonyl group and a lower alkylcarbonyl group preferably include the following groups. .

  In the groups exemplified above, OMe represents a methoxy group, and O-t-Bu represents a tert-butoxy group (the same applies hereinafter).

  a saturated heterocyclic ring constituting a part of each group described in (c15) to (c22) is a lower alkyl group, an aryl group, a cyanoaryl group, a lower alkylcarbonyl group, a halogeno-lower group on a nitrogen atom constituting the ring; As specific examples having any one substituent selected from the group consisting of an alkylaryl group and an aryl lower alkyl group, the following groups are preferably exemplified.

   A saturated heterocyclic ring constituting a part of each group described in the piperazino group (c5), piperidino group (c10) and (c15) to (c22) has a hydroxyl group, an oxo group on a carbon atom constituting these rings, As the group having any one substituent selected from the group consisting of a lower alkyl group, a hydroxy lower alkyl group, an aryl group, an aryl lower alkyl group, an aminocarbonyl group and a lower alkylamino group, preferably the following groups Can be illustrated.

  a saturated heterocycle of (c15) to (c22), wherein a lower alkyl group, an aryl group, a cyanoaryl group, a lower alkylcarbonyl group, a halogeno-lower alkylaryl group and an aryl-lower group are formed on the nitrogen atom constituting the saturated heterocycle; On each group having a substituent selected from the group consisting of alkyl groups, and carbon atoms constituting the saturated heterocyclic ring, a hydroxyl group, an oxo group, a lower alkyl group, a hydroxy lower alkyl group, an aryl group, an aryl lower alkyl group, Preferable examples of each group having a substituent selected from the group consisting of an aminocarbonyl group and a lower alkylamino group include the following groups.

  That is, as an amino group (c15) having a saturated heterocyclic ring and further having a substituent on the heterocyclic ring,

Etc. can be illustrated.

  As the lower alkylamino group (c16) having a saturated heterocyclic ring and further having a substituent on the heterocyclic ring,

Etc. can be illustrated.

  Piperazino group (c17) having a saturated heterocyclic ring, further having a substituent in the heterocyclic ring,

Etc. can be illustrated.

  As the lower alkyl piperazino group (c18) having a saturated heterocyclic ring, and further having a substituent on the heterocyclic ring,

Etc. can be illustrated.

  Piperidino group (c21) having a saturated heterocyclic ring, and further having a substituent on the heterocyclic ring,

Etc. can be illustrated.

  As the lower alkylmorpholino group (c22) having a saturated heterocyclic ring,

As examples of the group having a substituent on the nitrogen atom constituting the saturated heterocyclic ring,

Etc. can be illustrated.

Among the compounds of the present invention represented by the general formula (1), the first preferred compound group includes compounds in which R ² is a methylene group and R ³ is a hydrogen atom or a lower alkyl group. .

A second preferred compound group includes a compound group in which R ¹ is a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (3) or a group (6). Among these compounds, a more preferred compound is that R ⁴ is a lower alkylene group and Z ¹ is selected from (a2), (a14), (a15), (a28), (a32) and (a37) The compound which is any group can be mentioned.

As a third preferred group of compounds, R ¹ is a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (4), a group (5) or a group (7) (provided that Z ¹ Represents a lower alkoxycarbonyl group or a hydrogen atom).

A fourth preferred group of compounds includes compounds in which R ¹ is a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (8).

As a fifth preferred compound group, R ¹ is a hydrogen atom or a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (9), a group (10) or a group (11). A group of compounds can be mentioned.

As a sixth preferred group of compounds, R ¹ is a hydrogen atom or a lower alkylcarbonyl group, R ² is a methylene group, and R ³ is a group (9), a group (10) or a group (11) (provided that , Z ³ is (c1), (c2), (c4), (c5), (c6), (c7), (c8), (c10), (c11), (c15), (c16), (c18 ), (C21) or (c22)).

As a seventh preferred group of compounds, R ¹ is an acetyl group, R ² is a methylene group, and R ³ is a group (9) (wherein Z ³ is (c4), (c5), (c6) , (C10), (c11), (c16), (c18), (c21) or (c22)).

Specific examples of preferred compounds of the present invention include the compounds described in 1) to 19) below.
1) N- {4- [6-Amino-5-cyano-2- (pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
2) N- {4- [6-Amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
3) N- {4- [6-Amino-5-cyano-2- (6- {4- [2- (4-methylpiperazin-1-yl) acetyl] piperazin-1-ylmethyl} pyridin-2-yl Methylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
4) N- [4- (6-Amino-5-cyano-2- {6- [3- (4-methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidine- 4-yl) phenyl] acetamide
5) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl) propion Amide
6) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl)- N-methylpropionamide
7) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminopropyl)- N-methylpropionamide
8) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-methylpiperidine-1- Ylethyl) propionamide
9) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-diethylaminoethyl) propionamide
10) 3- {6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N-methyl-N- (1-methyl Piperidin-4-yl) propionamide
11) N- (4- {6-amino-2- [6- (3- [1,4 '] bipiperidinyl-1'-yl-3-oxopropyl) pyridin-2-ylmethylsulfanyl] -5-cyano Pyrimidin-4-yl} phenyl) acetamide
12) N- [4- (6-Amino-5-cyano-2- {6- [3-oxo-3- (2-piperidin-1-ylmethylmorpholin-4-yl) propyl] pyridin-2-yl Methylsulfanyl} pyrimidin-4-yl) phenyl] acetamide
13) N- {4- [6-Amino-5-cyano-2- (6- {3- [2- (4-ethylpiperazin-1-ylmethyl) morpholin-4-yl] -3-oxopropyl} pyridine -2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
14) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-diethylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-yl Methylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
15) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-diisopropylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridine-2- Ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
16) N- {4- [6-Amino-5-cyano-2- (6- {3-oxo-3- [4- (2-pyrrolidin-1-ylethyl) piperazin-1-yl] propyl} pyridine- 2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
17) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-morpholin-4-ylethyl) piperazin-1-yl] -3-oxopropyl} pyridine- 2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
18) N- {4- [6-Amino-5-cyano-2- (6- {3- [4- (2-diethylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-yl Methylsulfanyl) pyrimidin-4-yl] phenyl} acetamide
19) N- [4- (6-Amino-5-cyano-2- {6- [3- (4-methyl- [1,4] diazepan-1-yl) -3-oxopropyl] pyridine-2- Ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide.

  In the compound of the present invention, there may be a geometric isomer or tautomer based on a double bond or an amide bond depending on the type of substituent, but the present invention is a product obtained by separating these isomers, or Includes all mixtures.

  In addition, the compound of the present invention may have an asymmetric carbon atom. In this case, an optical isomer based on the asymmetric carbon atom may exist. The present invention includes a mixture of these optical isomers and an isolated product thereof.

  The present invention also includes a compound obtained by labeling the above-described compound of the present invention with a radioisotope.

The compounds of the present invention also include pharmacologically acceptable prodrugs. A pharmacologically acceptable prodrug refers to a compound having a group (protecting group) that can be converted to the compound of the present invention by solvolysis or under physiological conditions. Prodrug-forming groups are known (see, for example, Prog. Med., 5, 2157-2161, 1985, `` Drug Development '' (Yodogawa Shoten, 1990), Volume 7, Molecular Design pages 163-196, etc. ). Each of these groups can be converted into a functional group such as —NH ₂ , —OH, and —COOH by the above solvolysis and the like. Specifically, the compound of the present invention having the ethyl ester form, for example, the compound described in Example 43, can be converted to the compound of the present invention in the carboxylic acid form, that is, the compound of Example 45, by esterase in vivo.

  Furthermore, the compound of the present invention can form an acid addition salt or a salt with a base depending on the type of substituent. The present invention also includes such salts, particularly pharmaceutically acceptable acid addition salts and salts with bases. Specific examples of the acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, iohydric acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Mention may be made of acid addition salts with organic acids such as maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid. Specific examples of bases that form salts with bases include inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; organic bases such as methylamine, ethylamine, meglumine, and ethanolamine; lysine, arginine, ornithine, and the like. The basic amino acid can be mentioned. Salts with bases also include ammonium salts. These salts can be produced by a conventional method.

  Furthermore, the present invention also includes hydrates, solvates and crystalline polymorphs of the compounds of the present invention and pharmaceutically acceptable salts thereof.

Production of the Compound of the Present Invention Hereinafter, the production method of the compound of the present invention (including pharmaceutically acceptable salts thereof, hereinafter referred to as “the compound of the present invention” unless otherwise specified) will be described in detail.

The compound of the present invention can be produced by applying various known methods to the raw material compound according to the basic skeleton or the kind of substituent. At that time, depending on the type of functional group possessed by the target compound, the functional group possessed by the raw material compound (or intermediate compound) may be replaced with an appropriate protecting group (a group that can be easily converted into the functional group). May be effective in manufacturing technology. Examples of such a functional group include —NH ₂ , —OH, —COOH and the like. Examples of these protecting groups include protecting groups described in Greene and Wuts ("Protective Groups in Organic Synthesis" (3rd edition), 1999, John Wiley & Sons Inc.). be able to. The substitution reaction of the protecting group can be appropriately determined according to the reaction conditions described in the above-mentioned document, depending on the kind of the protecting group. In addition, a method in which the protecting group introduced by the above substitution reaction is eliminated from the target compound after obtaining the desired compound by a desired reaction can also be carried out according to a conventional method, for example, a method described in the above-mentioned literature.

  The compound of the present invention can be produced by the method shown in the following reaction process formula-1.

[In each formula, R ¹ , R ² and R ³ are the same as above, except that R ¹ is a hydrogen atom. X represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. ]
The compound (1) of the present invention is obtained from the aldehyde compound (compound (2a)) to the dicyanoethylene compound (compound (2b)) and the 2-mercaptopyrimidine compound (compound (2c)) or the 2-mercaptodihydropyrimidine compound (compound (2d)). ) Can be manufactured.

  The compound (2a) used here as a starting material is a known compound.

  In addition, compound (2d) includes isomers having different positions of endocyclic double bonds.

  Each reaction shown in Reaction Process Formula-1 can be carried out according to the methods described in the literature. More specifically, it can be carried out as follows.

  First, the reaction of compound (2a) and malononitrile (11) can be carried out according to the method described in the literature (see W. S. Emerson, T. M. Patrick, J. Org. Chem., 790, 14, 1949), for example. That is, an equimolar to excess molar amount of malononitrile (11) with respect to compound (2a) can be used without solvent or with water, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, tetrahydrofuran (THF), dioxane. , Acetone, methyl ethyl ketone (MEK), methanol, ethanol, methylene chloride, dichloroethane, chloroform and the like in a solvent inert to the reaction to give compound (2b). The above reaction is preferably carried out in an inert solvent, particularly in ethanol. The above reaction can be carried out without a catalyst, but is preferably carried out using a catalytic amount to an equimolar amount of catalyst with respect to compound (2a). Examples of the catalyst include organic bases such as piperidine and salts thereof, amino acids such as glycine, ammonium salts such as ammonium acetate, and the like. Of these, piperidine is particularly preferable. Regardless of whether or not a solvent and a catalyst are used as the temperature conditions for the above reaction, room temperature to heating conditions can be adopted in any case. In particular, it is preferable to use room temperature conditions.

  The compound (2b) obtained by the above reaction can be converted into the compound (2c), the compound (2d) or a mixture thereof by reacting with the thiourea (12). This reaction can be carried out, for example, according to literature methods (Daboun, H. A .; El-Reedy, A. M .; Z. Naturforsch., 1983, 38 (12), 1686). More specifically, using an equimolar to excess molar amount of thiourea (12) with respect to compound (2b), without solvent or with water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, The reaction can be carried out in a solvent inert to the reaction such as ethanol, acetonitrile, methylene chloride, dichloroethane, and chloroform. If desired, a base such as potassium carbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine and the like can be added to the reaction system. The above reaction is preferably carried out in ethanol in the presence of sodium ethoxide. The reaction temperature conditions for the above reaction may be from room temperature to heating conditions, and it is particularly preferable to employ a solvent heating reflux temperature condition.

  According to the method according to the reaction process formula-1, then the compound (2c) or the compound (2d) obtained by the above or a mixture thereof is added to the compound (13) (for example, halogen, arylsulfonyloxy group, alkylsulfonyloxy group, etc. The substituted pyridyl lower alkyl compound having a leaving group of the present invention can be reacted to produce the compound (1) of the present invention, its dihydro form (2e), or a mixture thereof. This reaction can be carried out using an equimolar amount to an excess molar amount of compound (13) with respect to compound (2c), compound (2d) or a mixture thereof. The reaction is carried out without solvent or in a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like. In the reaction system, a base such as potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine and the like may be further present as necessary. In the above, it is particularly preferable to carry out the reaction using DMF as a reaction solvent and in the presence of sodium hydrogen carbonate as a base. The reaction is generally carried out at room temperature to under heating, and a reaction at room temperature is particularly preferred.

The compound (13) used in the above reaction contains a new compound depending on the type of R ² group and R ³ group it has. This new compound will be described later.

  The dihydro form (2e) of the compound of the present invention obtained by the above reaction can be derived into the compound (1) of the present invention by further oxidizing the compound. This reaction is carried out in a catalytic amount to an excess molar amount of an oxidant such as DDQ (2,3-dichloro-5,6-dicyano-p-benzoquinone), NBS (N-bromosuccinimide) with respect to the dihydro form (2e). In a solvent inert to water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, ethyl acetate, methylene chloride, dichloroethane, chloroform, etc. Can be implemented. Thus, the compound (1) of the present invention can be obtained. This reaction is preferably carried out in the presence of DDQ using ethanol as the solvent and in the presence of NBS or using dioxane as the solvent. As the reaction temperature conditions, room temperature to heating conditions can be adopted, and the use of a solvent heating reflux temperature condition is particularly preferred.

  The compound of the present invention can also be produced by the method shown in the following reaction process formula-2.

[In each formula, R ¹ , R ² , R ³ and X are the same as those shown in the above reaction step formula-1. However, the case where R ¹ is a hydrogen atom is excluded. ]
According to the method shown in Reaction Scheme-2, the compound (1) of the present invention is obtained by reacting the compound (3a) produced by reacting the thiourea (12) with the compound (13) and the compound (2b). It can be produced via compound (2e). That is, the compound (1) of the present invention is obtained as a mixture with the compound (2e) via the compound (2e) (dihydropyrimidine form) by the above reaction.

  The compound (13) used here as a raw material includes both known compounds and novel compounds as described in the section of the reaction process formula-1. The new compound will be described later.

  Compound (2b) can be produced by reacting compound (2a) and compound (11) shown in the above reaction process formula-1.

  Compound (2e) includes isomers having different positions of endocyclic double bonds.

  In the method shown in Reaction Scheme-2, first, equimolar to excess molar amount of compound (13) is used with respect to thiourea (12), without solvent, or in water, DMF, DMSO, diethyl ether, THF. , Dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like are reacted in a solvent inert to the reaction. This reaction can be performed, for example, according to the synthesis method of S-alkylisothiourea described in the literature (Urquhart, G. G .; Gates, J. W. Jr; Connor, R .; Org. Synth., 1941, 21, 36). If necessary, a base such as potassium carbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine, or a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid may be added to the reaction system. obtain. As the reaction solvent, it is particularly preferable to use ethanol. The reaction can be carried out at room temperature to under heating, and it is particularly preferable to employ a heating condition of about 60 ° C. Thus, compound (3a) can be obtained in free form or in salt form.

  Then, the obtained compound (3a) (which may be in a free form or a salt form) is added with an equimolar amount to an excess molar amount of compound (2b) with respect to the compound without solvent or in DMF, DMSO, diethyl ether. , THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform, and the like in an inert solvent for the reaction, and if desired, an equimolar amount to an excess molar amount relative to the compound (3a) The reaction is carried out by adding a base such as potassium carbonate, sodium bicarbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine to the reaction system. This reaction can be performed according to a method described in the literature (El-Sharabsy, S. A .; Abdel Gawad, S. M .; Hussain, S. M .; J. Prakt. Chem., 1989, 331 (2), 207). In this reaction, ethanol can be exemplified as a particularly preferable solvent. In addition, it is preferable to add sodium hydrogen carbonate to the reaction system. The reaction can be carried out at room temperature to under heating, and it is particularly preferred to carry out the reaction under the conditions of heating and refluxing the solvent. In this way, this invention compound (1) or its dihydro form (2e) or these mixtures are obtained.

  The dihydro form (2e) of the compound of the present invention obtained above can be converted to the compound (1) of the present invention by an oxidation reaction according to the method shown in the reaction step formula-1.

  In the method shown in Reaction Scheme-2, compound (3a) is produced from thiourea (12), and after isolating the compound, compound (2b) is reacted with this compound, but compound (3a) is isolated. The compound (1) of the present invention, the dihydro form (2e) or a mixture thereof can also be obtained by adding the compound (2b) to the reaction system and reacting under the same conditions.

  The compound of the present invention can also be produced by the method shown in the following reaction process formula-3.

[In each formula, R ¹ , R ² , R ³ and X are the same as those shown in the above reaction step formula-1. However, the case where R ¹ is a hydrogen atom is excluded. ]
According to the method shown in Reaction Scheme-3, compound (2a) and malononitrile can be added to compound without isolating or isolating compound (3a) obtained by reacting thiourea (12) with compound (13). By reacting (11) at the same time, the compound (1) of the present invention or a dihydro form (2e) thereof or a mixture thereof can be obtained.

  The production reaction of compound (3a) is as shown in the above reaction process formula-2. The reaction of the compound (3a) with the compound (2a) and malononitrile (11) is carried out by reacting the compound (3a) (which may be in a free form or a salt form) with an equimolar amount to an excess molar amount with respect to the compound. Compound (2a) and an equimolar amount to an excess molar amount of malononitrile (11) are reacted under the same reaction conditions as in the case of the above reaction step formula-2 to give the present compound (1) or a dihydro form (2e) thereof or these Can be obtained.

  The dihydro form (2e) of the compound of the present invention obtained above can be converted to the compound (1) of the present invention by an oxidation reaction according to the method shown in the reaction step formula-1.

  Furthermore, this invention compound can be manufactured according to a well-known method by using the compound obtained according to the said various method as a raw material so that it may mention later.

Production of raw material compound The compound (13) used as a starting material in the above-mentioned reaction process formula-1 to reaction process expression-3 contains a new compound depending on the type of the R ² group and R ³ group possessed. These compounds can be produced, for example, according to each method described in the following reaction process formula-4 to reaction process formula-9.

[Wherein, X ¹ and X ² each represent a leaving group such as halogen, arylsulfonyloxy group, alkylsulfonyloxy group, etc. -NR ⁹ R ¹⁰

(In each group, Z ¹ , Z ² and R ⁵ are the same as those in the general formula (1)). ]
According to Reaction Scheme-4, R ² is a methylene group and R ³ is a group (3), a group (6) and a group (8). It can be produced by a reaction between a known compound (4a) and compound (15).

  In the reaction, compound (15) is usually used in an equimolar amount to an excess molar amount relative to compound (4a). The reaction can be performed without solvent or in a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like. In some cases, the reaction system contains an equimolar to excess molar amount of potassium carbonate, sodium bicarbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine, etc., relative to compound (4a). Can be present. Thus, compound (4b) is obtained. This reaction is preferably carried out in the absence of a base, using ethanol as a solvent and using an excess molar amount of compound (15) with respect to compound (4a). The reaction can be carried out at room temperature or under heating, and room temperature conditions are preferred.

[Where R ¹¹ is

(In each group, R ⁵ and Z ¹ are the same as those in the general formula (1)), R ¹² is a lower alkyl group, an aryl group or a halogeno lower alkyl group, and X is the same as in the above reaction process formula-1. . ]
According to Reaction Scheme-5, a starting material (compound (5e)) of the compound of the present invention in which R ² is a methylene group and R ³ is a group (4), a group (5) or a group (7) is produced. it can. Each reaction shown in this method can be carried out as follows. That is, a compound obtained from 6-methyl-2-picolinic acid (16) (or 6-methyl-3-picolinic acid, 6-methyl-4-picolinic acid, 6-methyl-5-picolinic acid) according to a conventional method ( 5a), an oxidizing agent such as m-chloroperbenzoic acid (m-CPBA) or hydrogen peroxide in a solvent inert to the reaction such as diethyl ether, THF, dioxane, acetonitrile, methylene chloride, dichloroethane, and chloroform. Is reacted with an equimolar amount to an excess molar amount with respect to compound (5a) to obtain compound (5b). As the reaction temperature, an ice-cold temperature or a solvent reflux temperature can be employed. In particular, this reaction is preferably carried out in chloroform at room temperature using an excess of an oxidizing agent such as m-CPBA.

  Next, to the compound (5b) obtained, an organic acid anhydride such as acetic anhydride in an equimolar amount to an excess molar amount with respect to the compound is added without solvent or in DMF, DMSO, diethyl ether, THF, dioxane, acetone. , MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like in a solvent inert to the reaction, and the reaction is carried out at room temperature to heating to give compound (5c).

  Further, the obtained compound (5c) is reacted with the compound (5c) in a solvent inert to the reaction such as water, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like. ) In the presence of a base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, sodium methoxide, sodium ethoxide, etc. The compound (5d) is obtained by hydrolysis reaction. This reaction is preferably followed by a method of heating to reflux with an excess amount of potassium hydroxide in methanol. The compound (5d) obtained by this reaction can also be obtained directly from the compound (5b) in one step. This reaction is carried out by adding equimolar to excess molar amount of trifluoroacetic anhydride to compound (5b), diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane, chloroform, etc. The reaction can be carried out by adding water, methanol, ethanol or the like after the reaction in a solvent inert to the reaction or without solvent. In particular, this reaction is preferably carried out by a method in which an excess molar amount of trifluoroacetic anhydride is reacted in the absence of a solvent and methanol is added and stirred.

  Finally, the reaction for obtaining the compound (5e) from the compound (5d) can be carried out by the following three methods.

  Method 1): An equimolar to excess molar amount of a halogenating agent such as thionyl chloride, thionyl bromide, or oxalyl chloride is added to compound (5d) without solvent or in diethyl ether, THF, dioxane, The reaction is carried out in a solvent inert to the reaction such as acetone, MEK, acetonitrile, methylene chloride, dichloroethane, and chloroform.

  Method 2): Compound (5d) is mixed with an alkylsulfonyl chloride such as methanesulfonyl chloride in an equimolar amount to an excess molar amount with respect to the compound without solvent or in diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, Equimolar to excess potassium carbonate, sodium bicarbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxy in an inert solvent for the reaction such as methylene chloride, dichloroethane, chloroform, etc. The reaction is carried out in the presence of a base such as tridoamine, triethylamine or diisopropylethylamine.

  Method 3): An equimolar amount to an excess molar amount of an alkyl halide such as carbon tetrachloride, chloroform, carbon tetrabromide, etc. with respect to the compound (5d), and an equimolar amount to an excess molar amount with respect to the compound (5d). In the presence of phosphine ligands such as triphenylphosphine and tri (n-butyl) phosphine in a solvent inert to reactions such as diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane, and chloroform. React.

[Wherein, R ¹³ represents a hydrogen atom or a protecting group, and R ¹⁴ represents a lower alkyl group. X is the same as the above reaction process formula-1. R ⁹ and R ¹⁰ are the same as in the above reaction process formula-4. ]
In the above, the protecting group represented by R ¹³ includes protecting groups usually used for protecting alcoholic hydroxyl groups such as an acetyl group, a methoxymethyl group, and a tetrahydropyranyl group.

According to reaction scheme-6, R ⁴ is an ethylene group, and R ³ is any one of groups (3), (6) and (8). ) Can be obtained. Each reaction in this method can be carried out as follows. That is, first, a compound (6a) having or not having a protecting group on the hydroxyl group, and an equimolar amount to an excess amount of trialkylsilylacetylene (17) with respect to the compound are reacted with a catalyst in a base such as triethylamine. The coupling reaction is carried out in the presence of an amount of an organometallic catalyst such as bis (triphenylphosphine) palladium chloride (II) and an activator such as copper (I) iodide. This reaction yields compound (6b).

Next, the compound (6b) is reacted with the compound (6b) in a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like. The compound (6c) is obtained by desilylation reaction in the presence of an equimolar to excess molar amount of a base such as potassium carbonate or sodium hydroxide. Depending on the type of the protecting group R ¹² , the above reaction may not be accompanied by the elimination reaction of the protecting group. In this case, the protecting group can be eliminated according to a conventional method.

  Further, to the obtained compound (6c), an equimolar amount to an excess molar amount of the compound (15) with respect to the compound is added with no solvent or DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol. , Acetonitrile, methylene chloride, dichloroethane, chloroform, etc., in an inert solvent, optionally equimolar to excess potassium carbonate, sodium bicarbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxy Compound (6d) is obtained by reacting in the presence of a base such as copper, triethylamine, diisopropylethylamine, etc. under ice-cooling or at the reflux temperature of the solvent. It is desirable to heat and reflux in ethanol together with an excess molar amount of compound (15).

  Finally, the desired compound (6e) is obtained by allowing the compound (6d) to undergo the same reaction as the synthesis reaction of the compound (5e) shown in the above reaction step formula-5.

[Wherein R ¹⁵ represents a lower alkoxy group. X is the same as the above reaction process formula-1. ]
According to the method shown in Reaction Scheme 7, R ² is a methylene group, R ³ is a group (9), and Z ³ is a (c2) lower alkoxy group. 7d)), and R ² is a methylene group, R ³ is a group (10), and Z ³ is (c2) a lower alkoxy group.The starting material of the compound of the present invention (compound (7e)) is synthesized. Can do.

  More specifically, in this method, compound (7b) is first obtained by reacting compound (7a) with an equimolar amount to an excess amount of acrylic acid lower alkyl ester (19). This reaction can be carried out according to the following two methods.

  That is, in a solvent-free or inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform, and in some cases inert gases such as argon and nitrogen. Under an active gas atmosphere, an equimolar amount to an excess amount of a base such as triethylamine and diisopropylethylamine and a catalytic amount to an equimolar amount of an organometallic catalyst such as palladium (II) acetate, bis (triphenylphosphine) palladium chloride and an equimolar amount. The compound (7a) and the compound (19) are reacted at room temperature or with heating in the presence of a phosphine ligand such as triphenylphosphine or tri (o-tolyl) phosphine in an excess amount (Heck reaction) (Method 1) ).

  Solvent-free or in inert solvents such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform, inert gases such as argon and nitrogen Under an atmosphere, an equimolar amount to an excess amount of potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine, diisopropylethylamine and other bases and an equimolar amount to an excess amount of tetrachloride ( n-butyl) ammonium, tetramethylammonium chloride and other phase transfer catalysts, catalytic amounts to equimolar amounts of palladium (II) acetate, organometallic catalysts such as bis (triphenylphosphine) palladium chloride, and optionally molecular sieves (Molecular Sieves) etc. In the presence of a dehydrating agent, reacting the compound at room temperature or heated (7a) with the compound (19) (Heck reaction, Jeffery condition) (Method 2).

  Among these, method 2, particularly in argon atmosphere, in DMF, equimolar amounts of tetra (n-butyl) ammonium chloride, excess sodium bicarbonate, excess molecular sieves (e.g. `` 3A 1/16 '' And the reaction in the presence of a catalytic amount of palladium (II) acetate at about 80 ° C. is desirable.

Then, the resulting compound (7b) was converted to a catalytic amount of platinum dioxide in a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, methanol, ethanol, acetonitrile, methylene chloride at room temperature or under heating. The compound (7c) is obtained by reacting with hydrogen gas under normal pressure or pressure in the presence of a catalytic reduction catalyst such as palladium-carbon. This reaction is particularly based on a method of vigorously stirring and reacting in methanol or ethanol at room temperature in the presence of a catalytic amount of platinum dioxide at atmospheric pressure or under pressure (1-3 kgf / cm ² ) in a hydrogen atmosphere. Is desirable.

  The compound (7c) thus obtained can be converted to the desired compound (7d) in the same manner as in the reaction for obtaining the compound (5e) from the compound (5d) shown in the above reaction step formula-5.

  In addition, compound (7e) can be obtained by performing a reaction similar to the reaction for obtaining compound (5e) from compound (5d) shown in reaction step formula-5 for compound (7b).

In the method shown in Reaction Scheme-7, if an appropriate starting material is used, R ² is a lower alkylene group, and R ³ is a group (9), a group (10) or a group (12). Starting material compounds of the compounds of the present invention can be synthesized.

[Wherein, R ¹⁵ is the same as the reaction process formula-7. Ph represents a phenyl group. ]
The compound (7b) shown in the above reaction process formula-7 is also represented by the Wittig reaction (A. Maercher, OR, using the known compound (8a) as a starting material, as shown in the above reaction process formula-8. 14,270 (1965) BEMaryanoff et al., CRV, 89, 863 (1989)) or Wittig-Horner reaction (reaction using a corresponding phosphonate instead of a phosphonium salt in the Wittig reaction).

  In the case of Wittig reaction, equimolar amount to excess amount of compound (8b) with respect to compound (8a), no solvent or DMF, diethyl ether, THF, dioxane, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform, etc. The desired compound (7b) is reacted with the compound (8a) in a solvent inert to the reaction of the compound, optionally under an inert gas atmosphere such as argon or nitrogen, under ice cooling, at room temperature or under heating. obtain. In particular, it is desirable to react an excess amount of compound (8b) in DMF. The Wittig-Horner reaction can be carried out in the same manner using an appropriate base such as the corresponding phosphonic acid ester and sodium methoxide instead of the compound (8b).

In the method shown in Reaction Scheme-8, if an appropriate starting material is used, R ² is a lower alkylene group, and R ³ is a group (9), a group (10) or a group (12). The starting material compound of the starting material of the compound of the present invention can be synthesized.

[Wherein R ¹⁶ is a hydrogen atom, or

[Wherein R ¹⁷ represents a lower alkyl group. ]
The starting material compounds of the present invention compounds in which R ² is and R ³ is a methylene group is (2) a lower alkyl group (Compound (9b)), R ² is a methylene group and R ³ is group (9) (where Z ³ is lower alkoxy (c2)) starting compound of the compound of the present invention (compound (9a)), and R ² is a methylene group and R ³ is a group (11) (provided that Z ³ is the 4-position) The starting material compound of the present compound (compound (9c)) having a lower alkyl group in (c5)-) can be produced according to the method shown in Reaction scheme-9.

  In this method, first, compound (9a) is obtained by subjecting compound (7a) to a coupling reaction with an equimolar amount to an excess amount of alkyne derivative (20) with respect to the compound. This reaction is carried out in an equimolar to excess amount of triethylamine in a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform, In the presence of a base such as diisopropylethylamine or t-butylamine, a catalytic amount of an organometallic catalyst such as tetrakis (triphenylphosphine) palladium (0) or palladium (II) chloride and an activator such as copper (I) iodide. It can be carried out in the presence of an inert gas atmosphere such as argon or nitrogen, in the presence of an antioxidant such as BHT (Butylhydroxytoluene). In particular, the reaction can be carried out at 80 ° C. in the presence of an excess amount of t-butylamine, a catalytic amount of tetrakis (triphenylphosphine) palladium (0), copper iodide (I) and BHT in an atmosphere of argon in DMF. desirable.

  Next, the obtained compound (9a) is subjected to a reaction similar to the reaction for converting the compound (7b) shown in the above reaction step formula-7 into the compound (7c), thereby obtaining the compound (9b).

  Furthermore, the desired compound (9c) can be obtained by performing a reaction similar to the reaction that leads the compound (5d) shown in the above reaction step formula-5 to the compound (5e). .

  Certain compounds in the compound of the present invention are produced according to various known synthetic methods using the compound of the present invention obtained according to the above-described various methods as a raw material and utilizing characteristics based on the basic skeleton or the type of substituent. You can also Hereinafter, the production method of the compound of the present invention will be described according to the following reaction process formulas -10 to -12.

[Wherein R ² and R ³ are the same as those in the general formula (1). R ^1a represents a lower alkylcarbonyl group. R ^1b represents a lower alkylcarbonyl group, a lower alkenylcarbonyl group or a phenylcarbonyl group. ]
As shown in Reaction Scheme-10, in the general formula (1), the compound of the present invention (compound 1B) in which R ¹ is a hydrogen atom is a compound of the present invention (1A) in which R ¹ is an alkylcarbonyl group such as an acetyl group. ) To compound (1A) in a solvent inert to the reaction such as water, DMF, DMSO, diethyl diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform, etc. Equimolar to excess molar amounts of potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide and other bases or hydrochloric acid, sulfuric acid, acetic acid, citric acid and other acids. By acting, it can be obtained by hydrolysis. The hydrolysis reaction can be carried out at room temperature or under heating. In particular, the hydrolysis reaction is preferably performed by adding an aqueous hydrochloric acid solution in a mixed solution of ethanol and water and stirring with heating at 80 ° C.

The compound (1C) of the present invention in which R ¹ is a lower alkylcarbonyl group, a lower alkenylcarbonyl group, or a phenylcarbonyl group, the compound (1B) of the present invention in which R ¹ is a hydrogen atom, DMSO, diethyl ether, THF, dioxane, In a solvent inert to the reaction such as acetone, MEK, acetonitrile, methylene chloride, dichloroethane, chloroform, etc., an equimolar to excess molar amount of potassium carbonate, sodium bicarbonate, sodium acetate, water with respect to the compound (1B) In the presence of a base such as sodium oxide, potassium hydroxide, triethylamine or diisopropylethylamine, an equimolar amount to an excess molar amount of an acylating agent such as an acid chloride or an active ester is allowed to act under ice-cooling or at room temperature to warming. Can be synthesized.

  In particular, this reaction is preferably carried out by reacting an excess amount of acid chloride at room temperature in acetonitrile in the presence of an excess amount of triethylamine.

[Wherein R ¹ , R ² and R ⁴ are the same as those in the general formula (1). Z ^1a represents (a12) a lower alkylcarbonyl group or (a28) a lower alkoxycarbonyl group. Z ^1b represents a Z ¹ group described in the general formula (1) excluding a hydrogen atom, that is, any one of the groups (a1) to (a31) or (a33) to (a38) described in the general formula (1). Show. ]
As shown in Reaction Process Formula-11, in the general formula (1), the present compound (1E) in which R ³ is a group (6) and Z ¹ is a (32) hydrogen atom is represented by the general formula (1) Wherein R ³ is a group (6) and Z ¹ is each group described in (a12) or (a28), that is, a group capable of leaving from the compound (1D) of the present invention which is a group capable of leaving. Can be synthesized by elimination reaction. More specifically, the compound (1D) of the present invention is mixed with water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like in an inert solvent. Or, in the absence of a solvent, an equimolar to excess molar amount of a base such as potassium carbonate, sodium hydrogen carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or the like with respect to the compound (1D) It can be obtained by acting and hydrolyzing a mineral acid such as hydrochloric acid and sulfuric acid or an organic acid such as acetic acid, trifluoroacetic acid and citric acid. The hydrolysis reaction can be carried out under any temperature condition of ice cooling temperature, room temperature and warming. Particularly preferred is a method in which Z ^1a is a BOC group (t-butoxycarbonyl group) and the mixture is stirred at room temperature using a solvent-free excess amount of trifluoroacetic acid.

In addition, as shown in reaction process formula-11, in general formula (1), R ³ is a group (6) and Z ¹ is selected from (a1) to (a31) or (a33) to (a38). In the general formula (1), R ³ is a group (6) and Z ¹ is a (32) hydrogen atom, depending on the type of Z ¹ group that the present compound (1F) is a group of It can be synthesized from the compound (1E) of the present invention as follows.

That is, equimolar to excess molar amount relative to compound (1E) in a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane, chloroform, etc. In the presence of a base such as potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, the compound (1E) is equimolar to excess molar amount of alkylcarbonyl chloride, arylcarbonyl. Z ¹ is the substituted carbonyl group described in (a12) to (a28) or (a36) to (a38) by allowing an acylating agent such as chloride or active ester to act on ice from room temperature to warming The compound of the present invention can be synthesized. It is preferable to react an excess molar amount of substituted carbonyl chloride in acetonitrile in the presence of an excess molar amount of triethylamine.

Various substituents in equimolar to excess molar amounts relative to compound (1E) in a solvent inert to the reaction such as DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane, and chloroform In the presence of a condensing agent such as DCC, WSC, BOP, DEPC, etc., in an equimolar amount to an excess molar amount with respect to compound (1E), optionally in an equimolar amount to an excess molar amount of HOSu, HOBt. In the present invention, Z ¹ is a substituted carbonyl group described in (a12) to (a28) or (a36) to (a38) by reacting with compound (1E) in the presence of an activator such as HOOBt. A compound can be obtained. The reaction can be carried out under any temperature condition of ice cooling temperature, room temperature and warming. In particular, the reaction is preferably carried out at room temperature in the presence of WSC and HOBt.

In a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane, chloroform, equimolar to excess molar amount of carbonic acid with respect to compound (1E). In the presence of a base such as potassium, sodium hydrogen carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, an equimolar to excess molar amount of a sulfonylating agent such as alkylsulfonyl chloride, arylsulfonyl chloride, etc. The compound of the present invention in which Z ¹ is each group described in (a29) to (a31) can be synthesized by acting on compound (1E). The reaction can be carried out under any temperature condition of ice cooling temperature, room temperature and warming. In particular, the reaction is preferably carried out in DMF in the presence of an excess molar amount of diisopropylethylamine at room temperature.

In a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane, chloroform, equimolar to excess molar amount of carbonic acid with respect to compound (1E). In the presence of a base such as potassium, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, triethylamine or diisopropylethylamine, an equimolar to excess molar amount of an alkyl halide such as an alkyl chloride, an alkyl such as an alkylmethane sulfonate A compound of the present invention in which Z ¹ is each group described in (a1) to (a11) or (a33) to (a35) is synthesized by allowing an agent (including an alkenylating agent) to act on compound (1E) it can. The reaction can be carried out under any temperature condition of ice cooling temperature, room temperature and warming. Particularly preferably, an excess of an alkylating agent, preferably an alkyl halide, is reacted at room temperature in DMF in the presence of an excess of potassium carbonate.

Corresponding to equimolar to excess molar amount of compound (1E) in solvents inert to reactions such as DMF, DMSO, diethyl ether, THF, dioxane, acetonitrile, methylene chloride, dichloroethane, chloroform, methanol, ethanol, etc. An aldehyde having a substituent to be reacted with compound (1E), optionally in the presence of a catalyst amount, such as acetic acid in an excess molar amount relative to compound (1E), and the resulting imine form is isolated or Without isolation, an equimolar amount to an excess molar amount of a reducing agent such as sodium cyanoborohydride, sodium cyanoborohydride, diborane, or the like is allowed to act on compound (1E), so that Z ¹ becomes (a1) to The compound of the present invention which is each group described in (a11) or (a33) to (a35) can be obtained (reductive alkylation). The reaction can be carried out under any temperature condition of ice cooling temperature, room temperature and warming. It is preferable to use a method in which an excess amount of aldehyde is reacted with compound (1E) at room temperature in the presence of 5 times the amount of acetic acid and an excess amount of sodium cyanoborohydride in DMF.

In the general formula (1), R ³ is a group (7) and Z ¹ is a hydrogen atom (a32) .In the general formula (1), R ³ is a group (8) and Z ² The compound of the present invention wherein is (b1) a hydrogen atom is a compound of the general formula (1) wherein R ³ is the group (7) and Z ¹ is any one of the groups described in (a12) or (28). Inventive compound and general formula (1), wherein R ³ is a group (8) and Z ² is a group described in (b2), the starting compound is a compound (1D ) From the reaction similar to the reaction for obtaining the compound (1E).

In the general formula (1), R ³ is a group (7) and Z ¹ is (a32) a hydrogen atom in the compound of the present invention and the general formula (1), R ³ is a group (8) and Using the compound of the present invention in which Z ² is a hydrogen atom (b1) as a raw material, a reaction similar to the reaction for obtaining the compound (1F) from the compound (1E) shown in the above reaction step formula-11, in the general formula (1), In the compound of the present invention and general formula (1), wherein R ³ is a group (7) and Z ¹ is any group described in (a1) to (a31) or (a33) to (a38), R ³ It is possible to produce a compound of the present invention wherein is a group (8) and Z ² is any group described in (b2) to (b8).

[Wherein R ¹ , R ² and R ⁴ are the same as those in the general formula (1). Z ^3a represents (c2) a lower alkoxy group. Z ^3b represents a Z ³ group described in the general formula (1) excluding a hydroxyl group and a lower alkoxy group, that is, any group of (c3) to (c22) described in the general formula (1). ]
As shown in Reaction Scheme-12, the compound (1H) of the present invention in which R ³ is a group (9) and Z ³ is a (c1) hydroxyl group, R ³ is a group (9) and Z ³ is a lower alkoxy It can be synthesized from the compound of the present invention (1G). This reaction is carried out by reacting, for example, the compound of the present invention (1G) with water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, chloroform and the like. A base or hydrochloric acid such as potassium carbonate, sodium hydrogen carbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, etc. It can be carried out by hydrolyzing with a mineral acid such as sulfuric acid or an organic acid such as acetic acid, trifluoroacetic acid or citric acid. The hydrolysis reaction proceeds at an ice-cold temperature, room temperature, or warming. In particular, it is preferable to employ a method in which Z ^3a is a solvent-free compound of the present invention in which tert-butoxy group is used and is stirred at room temperature using an excess amount of trifluoroacetic acid.

In addition, as shown in Reaction Process Formula-12, in the general formula (1), R ³ is a group (9) and Z ³ is a group selected from (c3) to (c22) ( 1I) can be synthesized from the compound (1H) of the present invention in which R ³ is group (9) and Z ³ is (c1) hydroxyl group. More specifically, this method is carried out with respect to the compound (1H) of the present invention in a solvent inert to the reaction such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane, and chloroform. The amine or aliphatic nitrogen-containing heterocyclic compound having the corresponding various substituents to give the desired Z ³ in an equimolar amount to an excess molar amount is converted into an equimolar amount to an excess molar amount of DCC with respect to the compound (1H) of the present invention. , WSC, BOP, DEPC, etc. in the presence of a condensing agent such as equimolar to excess molar amount of an activator such as HOSu, HOBt, HOOBt, etc. Can be implemented. Thus, the compound (1I) of the present invention in which Z ³ is a group selected from (c3) to (c22) can be obtained. The reaction can be carried out under any temperature conditions such as ice-cooling temperature, room temperature, and warming. As a particularly preferred method, there can be mentioned a method of reacting at room temperature in DMF or acetonitrile in the presence of BOP or WSC and HOBt.

In the general formula (1), R ³ is a group (10) and Z ³ is (c1) a hydrogen atom, and in the general formula (1), R ³ is a group (11) and Z ³ In the general formula (1), the compound of the present invention wherein R ³ is a group (12) and Z ³ is (c2) a lower alkoxy group and the general formula (1) Among them, using the compound of the present invention in which R ³ is the group (11) and Z ³ is (c2) a lower alkoxy group as a raw material, the reaction for obtaining the compound (1E) from the compound (1D) shown in the above reaction step formula-11 It can be synthesized by the same reaction.

Further, in the general formula (1), R ³ is a group (10) and Z ³ is (c1) a hydrogen atom, and in the general formula (1), R ³ is a group (11) and Using the compound of the present invention in which Z ³ is (c1) a hydrogen atom as a raw material, a reaction similar to the reaction for obtaining the compound (1F) from the compound (1E) shown in the above reaction step formula-11, in the general formula (1), In the compound of the present invention and general formula (1) wherein R ³ is a group (10) and Z ³ is any group described in (c3) to (c22), R ³ is a group (11) and The compound of the present invention in which Z ³ is any group described in (c3) to (c22) can be produced.

  The target compound and the compound of the present invention in each step shown in the above reaction process formulas can be isolated and purified as they are or as a salt thereof according to a conventional method. Examples of the isolation and purification means include ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatography.

  When the compound of the present invention exists as a mixture of isomers as described above, each isomer can be isolated by a conventional method utilizing the difference in physical properties between the isomers. More specifically, the resolution of a stereochemically pure isomer from a racemate is performed by optical resolution after forming a diastereomeric salt with a common racemic resolution method (a general optically active acid (such as tartaric acid)). Method). The resolution of each isomer from a mixture of diastereomers can be carried out according to, for example, fractional crystallization, chromatography or the like. The optically active compound of the present invention can also be produced by using an optically active raw material compound.

Pharmaceutical Composition The compounds of the present invention and salts thereof have an activity to activate adenosine A2a receptor, and are useful as adenosine A2a receptor agonists for mammals including humans in the pharmaceutical field. Accordingly, the present invention also provides a pharmaceutical composition suitable for pharmaceutical use such as such an adenosine A2a receptor agonist. Hereinafter, this pharmaceutical composition may be referred to as “the pharmaceutical composition of the present invention”.

  The pharmaceutical composition of the present invention is prepared and put into practical use in a general pharmaceutical preparation form containing at least one effective amount selected from the group consisting of the compound of the present invention and a salt thereof together with a pharmaceutically acceptable carrier. The The pharmaceutically acceptable carrier used in the pharmaceutical composition of the present invention may be a solid such as an excipient or a liquid such as a diluent. Specific examples of these carriers include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol and the like.

  In addition, the pharmaceutical composition of the present invention can be prepared in a dosage unit dosage form according to its administration application. Specific examples thereof include oral administration forms such as tablets, pills, capsules, granules, powders, liquids, and other solid and liquid forms, as well as injection forms such as intravenous injections and intramuscular injections, eye drops forms, and eyes. Examples include parenteral dosage forms such as ointment forms, suppository forms, and transdermal dosage forms. In particular, considering that the pharmaceutical composition of the present invention can be advantageously used as an intraocular pressure-lowering agent, a glaucoma therapeutic agent, etc. by utilizing its adenosine A2a receptor agonistic activity, an eye drop is preferable as the pharmaceutical composition form.

  This eye drop can be prepared, for example, as follows. That is, the compound of the present invention (including salts thereof, the same shall apply hereinafter), as required, isotonic agents such as sodium chloride and glycerin; stabilizers such as sodium edetate; antiseptics such as benzalkonium chloride and parabens Agent: Sodium hydrogen phosphate, sodium dihydrogen phosphate, boric acid, sodium tetraborate (borax), pH adjusters such as hydrochloric acid, sodium hydroxide, etc. To do.

  Preparation of solid preparations for oral administration that can be taken by the pharmaceutical composition of the present invention, such as tablets, powders, granules, etc., is carried out by preparing the compound of the present invention and at least one inert carrier such as lactose, mannitol, glucose, hydroxypropyl. It can be carried out by mixing cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid, magnesium aluminate and shaping the mixture according to a conventional method. The mixture further includes suitable additives, such as lubricants such as magnesium stearate; disintegrants such as calcium calcium glycolate; stabilizers such as lactose; solubilizing agents such as glutamic acid and aspartic acid. Etc. can be blended. Sweetening agents, flavoring agents, fragrances, preservatives and the like can also be added and blended. Tablets and pills may be further coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance, if necessary.

  Preparation of liquids for oral administration, such as emulsions, solutions, suspensions, syrups, elixirs, etc., is an inert diluent generally used with the compounds of the present invention, such as purified water, ethanol, etc. It can be carried out by dissolving or dispersing in the solution. In addition to this liquid agent, auxiliary agents such as wetting agents and suspending agents, sweeteners, flavors, fragrances, preservatives and the like can also be added and blended.

  Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, emulsions and the like. An aqueous injection can be prepared according to a conventional method using, for example, distilled water for injection and physiological saline as diluents. Non-aqueous injections can be prepared according to conventional methods using, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil; alcohols such as ethanol; polysorbate 80 and the like as diluents or carriers. These injections may further contain additives such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (for example, lactose), and solubilizing agents (for example, glutamic acid and aspartic acid). . The prepared injection is sterilized according to a conventional method, for example, filtration through a bacteria-retaining filter, blending of a bactericidal agent, or irradiation with radiation such as gamma rays. In addition, the injection can be prepared in a form of a dissolution solution at the time of use, which is practically used by dissolving a sterile solid preparation in sterile water or a sterile solvent for injection after production.

  The dosage of the pharmaceutical composition of the present invention prepared in various forms as described above is determined in consideration of the degree of symptoms, age, sex, etc. of the patient (administration subject) to which the pharmaceutical composition is applied. It is determined appropriately depending on the case. In general, the dosage of the pharmaceutical composition of the present invention in the form of eye drops is such that an eye drop having a concentration of the compound of the present invention as an active ingredient of 0.0001 to 10% (w / v%) is applied once to several times a day Alternatively, the amount can be applied to the eye. The amount of eye drops per one time is generally about 0.001 to 1 mL for an adult.

  When the pharmaceutical composition of the present invention is an oral preparation or an injection, the dosage can be 0.001 to 1000 mg per adult per day for the amount of the compound of the present invention as an active ingredient. The daily dose may be administered once a day, but it is usually preferable to administer the dose divided into several times a day. The above dose is only a guide and can be increased or decreased as appropriate. As described above, it is desirable that the dosage is appropriately determined each time according to various conditions. Therefore, depending on conditions, even when a dose further reduced from the above dose range is employed, a sufficient effect may be obtained.

  The compound of the present invention has an action to activate the adenosine A2a receptor (adenosine A2a receptor agonistic activity), and is useful for the prevention and / or treatment of glaucoma and ocular hypertension through the action of reducing intraocular pressure.

  Hereinafter, in order to describe the present invention in more detail, production examples of raw material compounds for the production of the compound of the present invention are given as reference examples, and then production examples of the compound of the present invention are given as examples. Moreover, the example of the pharmacological test conducted about this invention compound is given. These examples embody the present invention and are not intended to limit the scope of the present invention.

  In each example shown below, the nuclear magnetic resonance (NMR) spectrum was measured under the following conditions, and the abbreviations indicating the results are as follows.

Device: JNM-AL300 (manufactured by JEOL)
Internal standard: TMS
s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, sext: sextet
Moreover, the symbol used for each example shows the following.

IPE: Isopropyl ether
WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
LiAlH ₄ : Lithium aluminum hydride
THF: tetrahydrofuran
TBAF: Tetrabutylammonium fluoride
TBAF / THF solution: A mixture of tetrabutylammonium fluoride and tetrahydrofuran
DMF: N, N-dimethylformamide
HOBt: 1-hydroxybenzotriazole
m-CPBA: m-chloroperbenzoic acid
EtOH: ethanol
NBS: N-bromosuccinimide
DDQ: 2,3-dichloro-5,6-dicyano-p-benzoquinone
DMSO: Dimethyl sulfoxide
BOP and BOP reagents: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
TFA: trifluoroacetic acid.

Reference example 1
560 mg of (4-formylphenyl) carbamic acid methyl ester and 206 mg of malononitrile were dissolved in 10 mL of ethanol, 1 drop of piperidine was added to the resulting solution, and the mixture was stirred at room temperature for 3 hours. 10 mL of IPE was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain 441 mg of [4- (2,2-dicyanovinyl) phenyl] carbamic acid methyl ester.
Yellow powder
¹ H-NMR (CDCl ₃ ) δ: 7.90 (2H, d, J = 8.7 Hz), 7.65 (1H, s), 7.56 (2H, d, J = 8.7 Hz), 6.92 (1H, br s), 3.83 (3H, s).

Reference example 2
After adding 250 mg of metal sodium in 20 mL of absolute ethanol in small portions and completely dissolving, 760 mg of thiourea was added to the resulting solution, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 2.11 g of N-[-(2,2-dicyanovinyl) phenyl] acetamide was added and heated to reflux for 3 hours. Thereafter, the solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in 30 mL of water. Further, acetic acid was added to this solution little by little to make the solution acidic, and then 30 mL of ethyl acetate was added and stirred overnight. The precipitated insoluble matter was collected by filtration to obtain 1.2 g of N- [4- (6-amino-5-cyano-2-mercapto-2,3-dihydropyrimidin-4-yl) phenyl] acetamide.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 9.98 (1H, s), 9.65 (1H, br s), 7.56 (2H, d, J = 8.7 Hz), 7.14 (2H, d, J = 8.7 Hz) , 6.16 (2H, s), 4.92 (1H, s), 2.08 (3H, s).

Reference example 3
265 mg of 2,6-bis (bromomethyl) pyridine was suspended in 2 mL of ethanol, 87 mg of morpholine was added to the obtained suspension under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (methylene chloride-ethanol-triethylamine = 400: 20: 1 (v / v, hereinafter the same)) to obtain 90 mg of 4- (6- Bromomethylpyridin-2-ylmethyl) morpholine was obtained.
White powder
¹ H-NMR (CDCl ₃ ) δ: 10.0 (1H, s), 7.54-7.48 (2H, m), 7.42 (1H, s), 7.24 (1H, s), 4.08 (2H, t, J = 6.0 Hz ), 3.56 (2H, t, J = 4.5 Hz), 2.49 (2H, t, J = 7.2 Hz), 2.42-2.34 (4H, m), 1.89 (2H, quint., J = 6.6 Hz).

Reference example 4
(1) Acetic acid 6-bromopyridin-2-ylmethyl ester 2.3 g, trimethylsilylacetylene 1.18 g, bis (triphenylphosphine) palladium chloride (II) 210 mg, copper (I) iodide 114 mg and triethylamine 12 mL in an eggplant type flask And heated to reflux in an argon atmosphere for 5 hours. The reaction mixture was allowed to cool and then dried under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and 7 mL of methanol and 30 mL of 1N aqueous potassium hydroxide solution were added to the concentrate, followed by stirring for 1 hour. The reaction was acidified with 1N hydrochloric acid and concentrated under reduced pressure. The concentrate was basified with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The product thus obtained was purified by silica gel column chromatography (hexane-ethyl acetate = 4: 1) to obtain 212 mg of (6-ethynylpyridin-2-yl) methanol.
White powder
¹ H-NMR (CDCl ₃ ) δ: 7.67 (1H, t, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 4.76 (2H, d, J = 5.1 Hz), 3.38 (1H, t, J = 5.1 Hz), 3.18 (1H, s).

(2) 320 mg of (6-ethynylpyridin-2-yl) methanol and 1 g of morpholine were dissolved in 3 mL of ethanol and heated to reflux for 24 hours under an argon atmosphere. After allowing the reaction solution to cool, ethanol was distilled off under reduced pressure, and the residue was made basic by adding an aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia = 200: 10: 1) to obtain 122 mg of [6- (2-morpholin-4-ylethyl) pyridin-2-yl] methanol.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.60 (1H, t, J = 7.8 Hz), 7.08 (1H, d, J = 7.8 Hz), 7.03 (1H, d, J = 7.8 Hz), 4.72 (2H, s), 3.73 (4H, t, J = 4.5 Hz), 3.00 (2H, dd, J = 10, 8.7 Hz), 2.77 (2H, dd, J = 10, 8.7 Hz), 2.53 (4H, t, J = 4.5 Hz).

(3) 122 mg of [6- (2-morpholin-4-ylethyl) pyridin-2-yl] methanol and 104 mg of diisopropylethylamine were dissolved in 2.5 mL of dichloromethane, and 47 μL of methanesulfonic acid chloride was added dropwise to the solution under ice cooling. And stirred at room temperature overnight. After evaporating the solvent from the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia = 300: 10: 1) to obtain 80 mg of 4- [2- (6-chloromethylpyridine-2). -Yl) ethyl] morpholine was obtained.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.62 (1H, t, J = 7.8 Hz), 7.30 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 7.8 Hz), 4.64 (2H, s), 3.72 (4H, t, J = 4.8 Hz), 2.98 (2H, dd, J = 10, 8.7 Hz), 2.74 (2H, dd, J = 10, 8.7 Hz), 2.53 (4H, t, J = 4.8 Hz).

Reference Example 5
(1) 6.29 g of 6- (t-butyldimethylsilanyloxymethyl) pyridine-2-carboxaldehyde was dissolved in 50 mL of DMF, and 7.14 g of (carboethoxymethylene) triphenylphosphorane was added to the solution, and the mixture was stirred at room temperature for 1 hour. Stir. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness. To the residue was added 100 mL of a hexane-ethyl acetate (5: 1) mixture, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 10: 1) to obtain 5.45 g of 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] acrylic acid ethyl ester. Obtained.
Pale yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.72 (1H, t, J = 7.5 Hz), 7.66 (1H, d, J = 15.6 Hz), 7.49 (1H, d, J = 7.5 Hz), 7.29 (1H, d, J = 7.5 Hz), 6.88 (1H, d, J = 15.6 Hz), 4.83 (2H, s), 4.27 (2H, q, J = 7.2 Hz), 1.33 (3H, t, J = 7.2 Hz) , 0.97 (9H, s), 0.13 (6H, s).

(2) 3- [6- (t-Butyldimethylsilanyloxymethyl) pyridin-2-yl] acrylic acid ethyl ester (5.45 g) was dissolved in ethanol (100 mL), and platinum dioxide (200 mg) was added to the solution. The mixture was stirred at room temperature for 5 hours. After replacing the atmosphere of the reaction solution with nitrogen, the catalyst was filtered off from the reaction solution, the solvent was distilled off, and 5.07 g of 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] Propionic acid ethyl ester was obtained.
Pale yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.60 (1H, t, J = 7.5 Hz), 7.33 (1H, d, J = 7.5 Hz), 7.03 (1H, d, J = 7.5 Hz), 4.79 (2H, s), 4.12 (2H, q, J = 7.2 Hz), 3.07 (2H, t, J = 7.5 Hz), 2.75 (2H, t, J = 7.5 Hz), 1.23 (3H, t, J = 7.2 Hz) , 0.96 (9H, s), 0.11 (6H, s).

(3) Dissolve 5.07 g of 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] propionic acid ethyl ester in 100 mL of ethanol and add 23.5 mL of 1N aqueous sodium hydroxide solution to this solution. And stirred at room temperature for 2 hours. The reaction mixture was concentrated to about half volume under reduced pressure, ice water was added to the concentrate, and the mixture was made weakly acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol = 10: 1) to obtain 2.77 g of 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] propionic acid.
Colorless powder
¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, t, J = 7.5 Hz), 7.47 (1H, d, J = 7.5 Hz), 7.13 (1H, d, J = 7.5 Hz), 4.84 (2H, s), 3.15 (2H, t, J = 6.0 Hz), 2.82 (2H, t, J = 6.0 Hz), 0.96 (9H, s), 0.14 (6H, s).

(4) 1.65 g of 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] propionic acid is dissolved in 20 mL of methylene chloride, and 584 μL of morpholine, 1.6 g of WSC and 1.56 mL of triethylamine are dissolved in the solution. In addition, the mixture was stirred overnight at room temperature. The reaction mixture was diluted with chloroform, and the diluted solution was transferred to a separatory funnel and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol = 30: 1) to obtain 1.91 g of 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] -1-morpholine-4 -Ylpropan-1-one was obtained.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.60 (1H, t, J = 7.5 Hz), 7.33 (1H, d, J = 7.5 Hz), 7.08 (1H, d, J = 7.5 Hz), 4.79 (2H, s), 3.62-3.43 (8H, m), 3.11 (2H, t, J = 7.5 Hz), 2.77 (2H, t, J = 7.5 Hz), 0.96 (9H, s), 0.12 (6H, s).

(5) LiAlH ₄ 420 mg in a THF 20 mL suspension under ice-cooling, 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] -1-morpholin-4-ylpropane-1- 1.9 g of THF 30 mL solution was added dropwise. The reaction mixture was stirred at room temperature for 3 hours, water was added to deactivate excess LiAlH _4, and the mixture was filtered through Hyflo Supercell (manufactured by Nacalai Tesque) and separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride-ethanol = 40: 1) to obtain 760 mg of 4- {3- [6- (t-butyldimethylsilanyloxymethyl) pyridine- 2-yl] propyl} morpholine was obtained.

  Subsequently, 4- {3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] propyl} morpholine 760 mg in THF 4 mL solution was added to a 1 mol / L TBAF / THF solution 4.34 under ice cooling. mL was added dropwise. After stirring at room temperature for 2 hours, the solvent was distilled off, and the residue was purified by silica gel column chromatography (methylene chloride-ethanol = 40: 1) to obtain 495 mg of [6- (3-morpholin-4-ylpropyl) pyridine. -2-yl] methanol was obtained.

Further, 495 mg of the obtained [6- (3-morpholin-4-ylpropyl) pyridin-2-yl] methanol and 104 mg of diisopropylethylamine were dissolved in methylene chloride to prepare a 20 mL solution. Under ice cooling, 0.18 mL of methanesulfonic acid chloride was added dropwise and stirred overnight at room temperature. After the solvent was distilled off, the residue was purified by silica gel column chromatography (methylene chloride-ethanol = 40: 1) to obtain 290 mg of 4- [3- (6-chloromethylpyridin-2-yl) propyl] morpholine. It was.
Yellow powder
¹ H-NMR (CDCl ₃ ) δ: 7.57 (1H, t, J = 7.8 Hz), 7.05 (1H, d, J = 7.8 Hz), 7.02 (1H, d, J = 7.8 Hz), 4.65 (2H, s), 3.72 (4H, t, J = 4.8 Hz), 2.83 (2H, t, J = 7.8 Hz), 2.47-2.23 (6H, m), 1.96 (2H, quint., J = 7.8 Hz).

Reference Example 6
352 mg of 2,6-bis (chloromethyl) pyridine was suspended in 4 mL of ethanol, and 372 mg of N- (t-butoxycarbonyl) piperazine was added to the suspension under ice cooling, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 30: 1) to obtain 250 mg of 4- (6-chloromethylpyridin-2-ylmethyl) piperazine-1-carboxylic acid t-butyl ester .
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.69 (1H, t, J = 7.8 Hz), 7.37 (1H, dd, J = 7.8, 2.1 Hz), 4.66 (2H, s), 3.67 (2H, s), 3.45 (4H, t, J = 5.1 Hz), 2.45 (4H, t, J = 5.1 Hz), 1.48 (9H, s).

Reference Example 7
(1) 1.37 g of 6-methylpicolinic acid and 870 mg of morpholine were dissolved in 30 mL of DMF, and 1.6 g of HOBt was added to the solution while stirring under ice cooling. The mixture was stirred at the same temperature for 15 minutes, then 2.3 g of WSC was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 900: 30: 1) to obtain 1.71 g of (6-methylpyridin-2-yl) morpholin-4-ylmethanone. .
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.67 (1H, t, J = 7.8 Hz), 7.41 (1H, d, J = 7.8 Hz), 7.20 (1H, d, J = 7.8 Hz), 3.80 (4H, br s), 3.67-3.58 (4H, m), 2.57 (3H, s).

(2) Dissolve 1.38 g of (6-methylpyridin-2-yl) morpholin-4-ylmethanone in 10 mL of chloroform, add dropwise 23 mL of m-CPBA1.77 g of chloroform in this solution, and stir the mixture at room temperature for 1 day did. The reaction mixture was partitioned by adding 15 mL of a 10% aqueous sodium sulfite solution. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 1000: 25: 1) to obtain 1.26 g of (6-methyl-1-oxypyridin-2-yl) morpholine-4- Illmethanone was obtained.
White powder
¹ H-NMR (CDCl ₃ ) δ: 7.31-7.18 (3H, m), 3.94-3.64 (6H, m), 3.30-3.20 (1H, m), 3.18-3.12 (1H, m), 2.52 (3H, s).

(3) 0.53 mL of acetic anhydride was added to 1.26 g of (6-methyl-1-oxypyridin-2-yl) morpholin-4-ylmethanone, and the mixture was stirred at 100 ° C. for 1 hour. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 1000: 25: 1) to obtain 1.13 g of acetic acid 6- (morpholin-4-carbonyl) pyridin-2-ylmethyl ester.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.82 (1H, t, J = 7.8 Hz), 7.61 (1H, d, J = 7.8 Hz), 7.42 (1H, d, J = 7.8 Hz), 5.22 (2H, s), 3.82 (4H, br s), 3.67-3.65 (4H, m), 2.17 (3H, s).

(4) To 1.13 g of acetic acid 6- (morpholin-4-carbonyl) pyridin-2-ylmethyl ester were added 233 mg of potassium hydroxide and 1.5 mL of ethanol, and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the concentrate, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol-triethylamine = 500: 25: 1) to obtain 530 mg of (6-hydroxymethylpyridin-2-yl) morpholin-4-ylmethanone.
White powder
¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, t, J = 7.8 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz), 4.79 (2H, s), 3.82 (4H, br s), 3.68 (2H, t, J = 4.8 Hz), 3.58 (2H, t, J = 4.8 Hz).

(5) To a solution of (6-hydroxymethylpyridin-2-yl) morpholin-4-ylmethanone (530 mg) and diisopropylethylamine (614 mg) in methylene chloride (10 mL) was added dropwise methanesulfonic acid chloride (0.28 mL) under ice cooling, and the mixture was stirred at room temperature. Stir overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride-ethanol = 50: 1) to obtain 570 mg of (6-chloromethylpyridin-2-yl) morpholin-4-ylmethanone. Obtained.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.84 (1H, t, J = 7.8 Hz), 7.70 (1H, d, J = 7.8 Hz), 7.52 (1H, d, J = 7.8 Hz), 4.65 (2H, s), 3.82 (4H, br s), 3.69-3.65 (4H, m).

Reference Example 8
(1) 3.03 g of 6-methylpyridine-2-carboxylic acid t-butyl ester was dissolved in 30 mL of chloroform, and a solution of m-CPBA 3.96 g in 45 mL of chloroform was added dropwise to the resulting solution, and the mixture was stirred at room temperature overnight. . The reaction solution was transferred to a separating funnel, and 35 mL of a 10% Na ₂ SO ₃ aqueous solution was added to separate the solution. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 30: 1) to obtain 3.28 g of 6-methyl-1-oxypyridine-2-carboxylic acid t-butyl ester.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.29-7.13 (3H, m), 2.66 (3H, s), 1.63 (9H, s).
(2) To 3.28 g of 6-methyl-1-oxypyridine-2-carboxylic acid t-butyl ester was added 1.5 mL of acetic anhydride, and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 30: 1) to obtain 6-acetoxymethylpyridine-2-carboxylic acid t-butyl ester.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.94 (1H, d, J = 7.5 Hz), 7.80 (1H, t, J = 7.5 Hz), 7.50 (1H, d, J = 7.5 Hz), 5.32 (2H, s), 2.17 (3H, s), 1.58 (9H, s).

(3) To 3.0 g of 6-acetoxymethylpyridine-2-carboxylic acid t-butyl ester were added 330 mg of potassium carbonate, 20 mL of methanol and 20 mL of water, and the mixture was stirred at room temperature for 3 hours. Methanol was distilled off under reduced pressure, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-ethanol = 50: 1) to obtain 6-hydroxymethylpyridine-2-carboxylic acid t-butyl ester.
Yellow powder
¹ H-NMR (CDCl ₃ ) δ: 7.95 (1H, d, J = 7.5 Hz), 7.80 (1H, t, J = 7.5 Hz), 7.43 (1H, d, J = 7.5 Hz), 4.83 (2H, d, J = 5.1 Hz), 3.68 (1H, t, J = 5.1 Hz), 1.59 (9H, s).

(4) Dissolve 1.34 g of 6-hydroxymethylpyridine-2-carboxylic acid t-butyl ester and 1.24 g of diisopropylethylamine in 30 mL of methylene chloride, add 0.54 mL of methanesulfonyl chloride dropwise to this solution under ice cooling, and Stir overnight. After the solvent was distilled off from the reaction mixture, the residue was purified by silica gel column chromatography (hexane-ethyl acetate = 5: 1) to obtain 6-chloromethylpyridine-2-carboxylic acid t-butyl ester.
Yellow powder
¹ H-NMR (CDCl ₃ ) δ: 7.96 (1H, d, J = 7.5 Hz), 7.83 (1H, t, J = 7.5 Hz), 7.67 (1H, d, J = 7.5 Hz), 4.80 (2H, s), 1.59 (9H, s).

Reference Example 9
(1) Dissolve 6.15 g of 6-methylpicolinic acid and 3.21 g of t-butyl 1-piperazine carboxylate in 45 mL of DMF, add 4.24 g of HOBt to the solution under ice cooling, stir for 15 minutes, and then add 3.0 g of WSC. In addition, the mixture was stirred at room temperature overnight. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 30: 1) to obtain 4.57 g of 4- (6-methylpyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.67 (1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.21 (1H, d, J = 7.8 Hz), 3.77 (2H, t, J = 4.8 Hz), 3.55 (4H, t, J = 4.8 Hz), 3.46 (2H, t, J = 4.8 Hz), 2.57 (3H, s), 1.47 (9H, s).

(2) 4- (6-Methylpyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester (4.57 g) was dissolved in chloroform (30 mL), and m-CPBA (3.9 g) in chloroform (40 mL) was slowly added to the resulting solution. It was dripped. Thereafter, the mixture was stirred at room temperature for 1 day, and 35 mL of a 10% aqueous sodium sulfite solution was added to the reaction mixture for liquid separation. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 40: 1) to give 4.2 g of 4- (6-methyl-1-oxypyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester Got.
White powder
¹ H-NMR (CDCl ₃ ) δ: 7.31-7.17 (3H, m), 3.91 (1H, br s), 3.62-3.56 (4H, m), 3.45 (1H, br s), 3.26 (1H, br s ), 3.13 (1H, br s), 2.51 (3H, s), 1.47 (9H, s).

(3) To 4.2 g of 4- (6-methyl-1-oxypyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester was added 1.2 mL of acetic anhydride, and the mixture was stirred at 100 ° C. for 1 hour. After cooling, the reaction solution was neutralized with a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 40: 1) to obtain 3.7 g of 4- (6-acetoxymethylpyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester .
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.82 (1H, t, J = 7.8 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.40 (1H, d, J = 7.8 Hz), 5.22 (2H, s), 3.77 (2H, t, J = 4.8 Hz), 3.59-3.56 (4H, br), 3.69 (2H, t, J = 4.8 Hz), 2.17 (3H, s), 1.47 (9H, s).

(4) 840 mg of potassium hydroxide was added to 10 mL of a methanol solution of 3.7 g of 4- (6-acetoxymethylpyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester, and the mixture was heated to reflux for 4 hours. After distilling off the solvent, water was added to the solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 50: 1) to obtain 1.26 g of 4- (6-hydroxymethylpyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester .
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, t, J = 7.8 Hz), 7.55 (1H, d, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 4.79 (2H, s), 3.79 (2H, t, J = 4.8 Hz), 3.58-3.45 (6H, br), 1.47 (9H, s).

(5) 1.26 g of 4- (6-hydroxymethylpyridine-2-carbonyl) piperazine-1-carboxylic acid t-butyl ester and 1.0 g of diisopropylethylamine are dissolved in 20 mL of methylene chloride, and methanesulfone is added to the solution under ice cooling. 0.1 mL of acid chloride was added dropwise and the mixture was stirred at room temperature overnight. After removing the solvent from the reaction mixture under reduced pressure, the residue was purified by silica gel column chromatography (methylene chloride-ethanol = 40: 1) to give 1.07 g of 4- (6-chloromethylpyridine-2-carbonyl) piperazine-1 -Carboxylic acid t-butyl ester was obtained.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.84 (1H, t, J = 7.8 Hz), 7.60 (1H, d, J = 7.8 Hz), 7.54 (1H, d, J = 7.8 Hz), 4.66 (2H, s), 3.76 (2H, br), 3.57-3.48 (6H, br), 1.47 (9H, s).

Reference Example 10
(1) 15.3 g of 6-hydroxymethylpyridine-2-carbaldehyde was dissolved in 250 mL of dry DMF, and 50 g of (t-butoxycarbonylmethylene) triphenylphosphorane was added to the solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 300 mL of a hexane-ethyl acetate (2: 1) mixture, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1) to give 16.86 g of 3- (6-hydroxymethylpyridin-2-yl) trans-acrylic acid t- The butyl ester and 5.69 g of 3- (6-hydroxymethylpyridin-2-yl) cis-acrylic acid t-butyl ester were obtained.
trans form: colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.70 (1H, t, J = 7.5 Hz), 7.58 (1H, d, J = 15.6 Hz), 7.31 (1H, d, J = 7.5 Hz), 7.18 (1H, d, J = 7.5 Hz), 6.88 (1H, d, J = 15.6 Hz), 4.77 (2H, d, J = 4.8 Hz), 3.88 (1H, t, J = 4.8 Hz), 1.54 (9H, s) .
cis body: colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.67 (1H, t, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz), 6.86 (1H, d, J = 12.6 Hz), 6.07 (1H, d, J = 12.6 Hz), 4.74 (2H, d, J = 4.8 Hz), 3.77 (1H, t, J = 4.8 Hz), 1.46 (9H, s) .

(2) Dissolve 16.86 g of 3- (6-hydroxymethylpyridin-2-yl) trans-acrylic acid t-butyl ester (trans form) in 200 mL of ethanol, add 0.5 g of platinum dioxide to the solution, The mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. Thereafter, the catalyst was removed by filtration, 0.5 g of platinum dioxide was newly added, and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere at normal pressure. The catalyst was removed from the reaction mixture by filtration, and the solvent was distilled off under reduced pressure to obtain 16.13 g of 3- (6-hydroxymethylpyridin-2-yl) propionic acid t-butyl ester.
Pale yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.58 (1H, t, J = 7.5 Hz), 7.08 (1H, d, J = 7.5 Hz), 7.03 (1H, d, J = 7.5 Hz), 4.70 (2H, s), 3.10 (2H, t, J = 7.5 Hz), 2.72 (2H, t, J = 7.5 Hz), 1.42 (9H, s).

(3) Dissolve 16.13 g of 3- (6-hydroxymethylpyridin-2-yl) propionic acid t-butyl ester in 200 mL of dry methylene chloride, add 33.8 g of carbon tetrabromide to the solution, and further under ice cooling. While stirring, 21.5 g of triphenylphosphine was added little by little and stirred at the same temperature for 30 minutes. The reaction mixture was transferred to a separatory funnel, washed with a saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 200 mL of a hexane-ethyl acetate (2: 1) mixture, the precipitated insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 5: 1) to obtain 14.12 g of 3- (6-bromomethylpyridin-2-yl) propionic acid t-butyl ester.
Pale yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.58 (1H, t, J = 7.5 Hz), 7.26 (1H, d, J = 7.5 Hz), 7.09 (1H, d, J = 7.5 Hz), 4.51 (2H, s), 3.06 (2H, t, J = 7.5 Hz), 2.70 (2H, t, J = 7.5 Hz), 1.42 (9H, s).

Reference Example 11
(1) 2 g of 2-bromopyridine-6-methanol was dissolved in 10 mL of dry DMF, and 1.73 mL of ethyl acrylate, 2.95 g of tetra (n-butyl) ammonium chloride, 1.78 g of sodium bicarbonate and molecular sieves (Molecular 2 g of Sieves 3A (1/16)) was added, and 119 mg of palladium (II) acetate was further added under an argon atmosphere, and the mixture was stirred at 80 ° C. for 5 hours. After cooling, the insoluble material was removed by filtration, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 2: 1) to obtain 1.39 g of 3- (6-hydroxymethylpyridin-2-yl) trans-acrylic acid ethyl ester.
Pale yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.71 (1H, t, J = 7.5 Hz), 7.66 (1H, d, J = 15.6 Hz), 7.32 (1H, d, J = 7.5 Hz), 7.20 (1H, d, J = 7.5 Hz), 6.96 (1H, d, J = 15.6 Hz), 4.78 (2H, d, J = 4.8 Hz), 4.29 (2H, q, J = 7.2 Hz), 3.85 (1H, t, J = 4.8 Hz), 1.35 (3H, t, J = 7.2 Hz).

(2) 3- (6-hydroxymethylpyridin-2-yl) trans-acrylic acid ethyl ester was reduced by the same method as described in Reference Example 10- (2) to give 3- (6-hydroxy Methylpyridin-2-yl) propionic acid ethyl ester was obtained.
Pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 7.58 (1H, t, J = 7.5 Hz), 7.08 (1H, d, J = 7.5 Hz), 7.02 (1H, d, J = 7.5 Hz), 4.71 (2H, d, J = 4.5 Hz), 4.14 (2H, q, J = 7.2 Hz), 4.01 (1H, t, J = 4.5 Hz), 3.15 (2H, t, J = 7.5 Hz), 2.80 (2H, t, J = 7.5 Hz), 1.24 (3H, t, J = 7.2 Hz).

Reference Example 12
(1) 3- (6-hydroxymethylpyridin-2-yl) trans-methyl acrylate in the same manner as described in Reference Example 11- (1) using methyl acrylate instead of ethyl acrylate An ester was obtained.
Pale yellow powder
¹ H-NMR (CDCl ₃ ) δ: 7.72 (1H, t, J = 7.5 Hz), 7.68 (1H, d, J = 15.6 Hz), 7.32 (1H, d, J = 7.5 Hz), 7.21 (1H, d, J = 7.5 Hz), 6.97 (1H, d, J = 15.6 Hz), 4.78 (2H, d, J = 4.2 Hz), 3.85 (1H, t, J = 4.2 Hz), 3.83 (3H, s) .

(2) 3- (6-hydroxymethylpyridin-2-yl) trans-acrylic acid methyl ester was reduced by the same method as described in Reference Example 10- (2) to give 3- (6-hydroxy Methylpyridin-2-yl) propionic acid methyl ester was obtained.
Light brown oil.
¹ H-NMR (CDCl ₃ ) δ: 7.58 (1H, t, J = 7.5 Hz), 7.09 (1H, d, J = 7.5 Hz), 7.03 (1H, d, J = 7.5 Hz), 4.71 (2H, s), 4.01 (1H, br s), 3.69 (3H, s), 3.15 (2H, t, J = 7.2 Hz), 2.81 (2H, t, J = 7.2 Hz).

  This compound was also synthesized by the following method.

That is, 50.02 g of 3- (6-hydroxymethylpyridin-2-yl) trans-acrylic acid methyl ester was dissolved in 502 mL of IPA, and after argon substitution, 2.51 g of 5% palladium-carbon (containing 50% water) was added to this solution. In addition, the mixture was stirred at 50 ° C. for 2.5 hours under a hydrogen atmosphere of 1 to 4 atm. After cooling, the catalyst was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the target compound 3- (6-hydroxymethylpyridin-2-yl) propionic acid methyl ester as a light brown yellow powder. This compound was further identified by ¹ H-NMR (CDCl ₃ ) analysis.

Reference Example 13
(1) 2.95 g of 6-hydroxymethylpyridine-2-carbaldehyde and 5.12 g of triethyl 2-phosphonopropionate are dissolved in 20 mL of dry DMF, and a solution of sodium methoxide 1.30 g in 10 mL of methanol is added dropwise to the solution. For 20 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1) to give 2.42 g of (E) -3- (6-hydroxymethylpyridin-2-yl) -2-methylacrylic acid ethyl ester Got.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.71 (1H, t, J = 7.8 Hz), 7.63 (1H, q, J = 1.5 Hz), 7.29 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz), 4.79 (2H, d, J = 4.8 Hz), 4.29 (2H, q, J = 7.2 Hz), 3.84 (1H, t, J = 4.8 Hz), 2.35 (3H, d, J = 1.5 Hz), 1.36 (3H, t, J = 7.2 Hz).

(2) (E) -3- (6-Hydroxymethylpyridin-2-yl) -2-methylacrylic acid ethyl ester was reduced according to the same method as described in Reference Example 10- (2), 3- (6-Hydroxymethylpyridin-2-yl) -2-methylpropionic acid ethyl ester was obtained.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.57 (1H, t, J = 7.5 Hz), 7.04 (1H, d, J = 7.5 Hz), 7.02 (1H, d, J = 7.5 Hz), 4.70 (2H, br s), 4.11 (2H, q, J = 7.2 Hz), 3.22 (1H, dd, J = 14.1, 7.8 Hz), 3.05 (1H, sextet, J = 6.3 Hz), 2.88 (1H, dd, J = 14.1, 6.3 Hz), 1.27-1.16 (6H, m).

Reference Example 14
2 g of 3- (6-hydroxymethylpyridin-2-yl) trans-acrylic acid t-butyl ester (trans form) described in Reference Example 10- (1) and 4.23 g of carbon tetrabromide were dissolved in methylene chloride. 2.68 g of triphenylphosphine was added little by little to 20 mL of the solution prepared under ice cooling, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was transferred to a separatory funnel, diluted with chloroform, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 10: 1) to obtain 2.23 g of 3- (6-bromomethylpyridin-2-yl) trans-acrylic acid t-butyl ester.
Pale yellow powder
¹ H-NMR (CDCl ₃ ) δ: 7.70 (1H, t, J = 7.8 Hz), 7.56 (1H, d, J = 15.6 Hz), 7.41 (1H, d, J = 7.8 Hz), 7.32 (1H, d, J = 7.8 Hz), 6.87 (1H, d, J = 15.6 Hz), 4.54 (2H, s), 1.53 (9H, s).

Reference Example 15
(1) 1.03 g of 4-pentinoic acid and 1.0 g of N-methylpiperazine were dissolved in 30 mL of DMF, and 1.6 g of HOBt was added to the solution while stirring under ice cooling. After stirring for 15 minutes at the same temperature, 2.3 g of WSC was further added and stirred overnight at room temperature. After DMF was distilled off from the reaction mixture under reduced pressure, water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 600: 20: 1) to give 510 mg of 1- (4-methylpiperazin-1-yl) pent-4-yn-1-one. It was.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 3.64 (2H, t, J = 5.1 Hz), 3.48 (2H, t, J = 5.1 Hz), 2.59-2.52 (4H, m), 2.41-2.35 (4H, m ), 2.30 (3H, s), 1.97 (1H, s).

(2) In a 50 mL round-bottom flask, 2-bromopyridin-6-methanol 484 mg, 1- (4-methylpiperazin-1-yl) pent-4-in-1-one 510 mg, BHT 20 mg, copper iodide ( I) 162 mg, tetrakis (triphenylphosphine) palladium (0) 118 mg, t-butylamine 375 mg and DMF 7.5 mL were added and the mixture was stirred at 80 ° C. for 6 hours under argon atmosphere. DMF was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 600: 20: 1) to give 540 mg of 5- (6-hydroxymethylpyridin-2-yl) -1- (4-methylpiperazine-1 -Yl) pent-4-yn-1-one was obtained.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.62 (1H, t, J = 7.8 Hz), 7.27 (1H, d, J = 7.8 Hz), 7.18 (1H, d, J = 7.8 Hz), 4.73 (2H, s), 3.67 (2H, t, J = 6.6 Hz), 3.53 (2H, t, J = 6.6 Hz), 2.84-2.78 (2H, m), 2.72-2.67 (2H, m), 2.43-2.38 (4H m), 2.30 (3H, s).

Reference Example 16
(1) In a 200 mL round bottom flask, 3.49 g of 2-bromopyridine-6-methanol, 3.0 g of 4-pentinoic acid t-butyl ester, 190 mg of BHT, 1.17 g of copper (I) iodide, tetrakis (triphenylphosphine) 877 mg of palladium (0), 2.72 g of t-butylamine and 56 mL of DMF were added, and the mixture was stirred at 80 ° C. for 6 hours under an argon atmosphere. After distilling off DMF from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate = 2: 1) to obtain 2.76 g of 5- (6-hydroxymethylpyridin-2-yl) pent-4-ynoic acid t-butyl ester. Obtained.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.61 (1H, t, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.17 (1H, d, J = 7.8 Hz), 4.72 (2H, d, J = 5.1 Hz), 3.32 (1H, t, J = 5.1 Hz), 2.75 (2H, t, J = 7.2 Hz), 2.57 (2H, t, J = 7.2 Hz), 1.45 (12H, s) .

(2) To a 200 mL round bottom flask, add 2.76 g of 5- (6-hydroxymethylpyridin-2-yl) pent-4-ynoic acid t-butyl ester, 50 mg of platinum dioxide and 25 mL of EtOH. Was stirred at room temperature for 8 hours. The insoluble material was removed by filtration, and the filtrate was concentrated to obtain 2.78 g of 5- (6-hydroxymethylpyridin-2-yl) pentanoic acid t-butyl ester.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.57 (1H, t, J = 7.8 Hz), 7.02 (2H, t, J = 7.8 Hz), 4.71 (2H, s), 2.80 (2H, t, J = 7.2 Hz), 2.56 (2H, t, J = 7.2 Hz), 1.82-1.60 (4H, m), 1.42 (12H, s).

(3) In a 200 mL round bottom flask, add 50 mL of dichloromethane, add 2.78 g of 5- (6-hydroxymethylpyridin-2-yl) pentanoic acid t-butyl ester and 2.0 g of diisopropylethylamine, and cool the mixture under ice cooling. Stir for 10 minutes. To the reaction mixture, 0.89 mL of methanesulfonic acid chloride was added dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture for liquid separation, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane-ethyl acetate = 3: 1) to obtain 2.28 g of 5- (6-methanesulfonyloxymethylpyridin-2-yl) pentanoic acid t-butyl ester.
Yellow oil
¹ H-NMR (CDCl ₃ ) δ: 7.65 (1H, t, J = 7.8 Hz), 7.30 (1H, d, J = 7.8 Hz), 7.13 (1H, d, J = 7.8 Hz), 5.29 (2H, s), 3.08 (3H, s), 2.80 (2H, t, J = 7.2 Hz), 2.25 (2H, t, J = 7.2 Hz), 1.75-1.50 (4H, m), 1.44 (12H, s).

Reference Example 17
(1) (E) -1- (6-hydroxymethylpyridin-2-yl) pent-1-ene was prepared in the same manner as described in Reference Example 11 using ethyl vinyl ketone instead of ethyl acrylate. -3-one was obtained.
Colorless oil
¹ H-NMR (CDCl ₃ ) δ: 7.72 (1H, t, J = 7.5 Hz), 7.55 (1H, d, J = 15.6 Hz), 7.36 (1H, d, J = 7.5 Hz), 7.23 (1H, d, J = 15.6 Hz), 7.22 (1H, d, J = 7.5 Hz), 4.79 (2H, d, J = 4.5 Hz), 3.84 (1H, br t, J = 4.5 Hz), 2.74 (2H, q , J = 7.2 Hz), 1.18 (3H, t, J = 7.2 Hz).

(2) Reduction of (E) -1- (6-hydroxymethylpyridin-2-yl) pent-1-en-3-one according to the same method as described in Reference Example 10- (2) 1- (6-hydroxymethylpyridin-2-yl) pentan-3-one was obtained.
Light brown oil.
¹ H-NMR (CDCl ₃ ) δ: 7.57 (1H, t, J = 7.8 Hz), 7.09 (1H, d, J = 7.8 Hz), 7.02 (1H, d, J = 7.8 Hz), 4.70 (2H, s), 3.94 (1H, br s), 3.09 (2H, t, J = 6.9 Hz), 2.92 (2H, t, J = 6.9 Hz), 2.47 (2H, q, J = 7.2 Hz), 1.06 (3H , t, J = 7.2 Hz).

The structures of the compounds obtained in Reference Examples 1 to 17- (2) are summarized in Tables 1 to 5 below. In addition, the symbol in a table | surface shows each following group. In each table in the following specification, the abbreviations used have the same meaning.
MeO and OMe: methoxy group,
Me: methyl group
Et: ethyl group
AcO and OAc: acetyloxy group,
TBDMS: tert-butyldimethylsilyl group,
OEt and EtO: ethoxy group,
OtBu and tBuO: tert-butyloxy group,
Ac: acetyl group,
tBu and t-Bu: tert-butyl group
n-Pr: n-propyl group,
iPr and i-Pr: isopropyl group,
Ph: Phenyl group
n-Bu: n-butyl group
i-Bu: 2-methylpropyl group

285 mg of the compound obtained in Reference Example 2, 172 mg of 2- (chloromethyl) pyridine hydrochloride, 184 mg of sodium bicarbonate and 157 mg of sodium iodide were added to 3 mL of DMF, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride-ethanol = 40: 1) to give 31 mg of N- {4- [6-Amino-5-cyano-2- (pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 8.51 (1H, d, J = 4.8 Hz), 7.83 (2H, d, J = 8.4 Hz), 7.75-7.70 (3H, m ), 7.54 (1H, d, J = 7.8Hz), 7.26 (1H, dd, J = 6.6, 4.8Hz), 4.50 (2H, s), 2.08 (3H, s).

  5 g of 6-methyl-2-pyridinemethanol was dissolved in 50 mL of methylene chloride, 10.6 mL of diisopropylethylamine was added to the solution, and 3.5 mL of methanesulfonyl chloride was further added dropwise with stirring with ice cooling. After stirring with ice cooling for 1 hour, water was added to the reaction solution, and the organic layer was washed twice with water and once with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off to obtain 6.98 g of a brown oil.

Of this, 4.56 g was dissolved in 50 mL of ethanol, 1.72 g of thiourea was added to this solution, and the mixture was heated to reflux for 1 hour. Next, 20 mL of ethanol was added to the reaction solution to cool, and 4.79 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 3 g of sodium hydrogen carbonate were added, and the mixture was heated to reflux for 1.5 hours. After allowing the reaction solution to cool, 2.02 g of NBS was added to the solution and heated to reflux for 30 minutes. The reaction solution was allowed to cool, further diisopropyl ether was added, the precipitated inorganic matter was filtered off, the mother liquor was concentrated and dissolved again in ethanol. Saturated aqueous sodium bicarbonate solution was added to this solution, and the precipitated crystals were collected by filtration. The obtained crystals were washed with water and ethanol, dried under reduced pressure, and 3.2 g of N- {4- [6-amino-5-cyano- 2- (6-Methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.60 (1H, t, J = 7.5 Hz), 7.33 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 4.44 (2H, s), 2.45 (3H, s), 2.09 (3H, s).

N- {4- [6-amino-5-cyano-2] was prepared in the same manner as described in Example 2, using 5-methyl-2-pyridinemethanol instead of 6-methyl-2-pyridinemethanol. -(5-Methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 8.34 (1H, s), 7.60-8.20 (2H, br s), 7.84 (2H, d, J = 8.7 Hz), 7.72 ( 2H, d, J = 8.7 Hz), 7.54 (1H, d, J = 7.8 Hz), 7.43 (1H, d, J = 7.8 Hz), 4.46 (2H, s), 2.26 (3H, s), 2.09 ( 3H, s).

N- {4- [6-amino-5-cyano-2] was used in the same manner as described in Example 2 except that 4-methyl-2-pyridinemethanol was used instead of 6-methyl-2-pyridinemethanol. -(4-Methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 8.62 (1H, s), 7.65-8.25 (2H, br s), 7.84 (2H, d, J = 8.7 Hz), 7.73 ( 2H, d, J = 8.7 Hz), 7.36 (1H, s), 7.00 (1H, d, J = 7.8 Hz), 4.56 (2H, s), 2.26 (3H, s), 2.09 (3H, s).

N- {4- [6-amino-5-cyano-2] was used in the same manner as described in Example 2, using 3-methyl-2-pyridinemethanol instead of 6-methyl-2-pyridinemethanol. -(3-Methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 8.34 (1H, d, J = 4.8 Hz), 7.70-8.25 (2H, br s), 7.87 (2H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.7 Hz), 7.60 (1H, d, J = 7.5 Hz), 7.19-7.24 (1H, m), 4.61 (2H, s), 2.36 (3H, s), 2.09 (3H, s).

In the same manner as described in Example 2, using 1- (6-methylpyridin-2-yl) ethanol instead of 6-methyl-2-pyridinemethanol, N- (4- {6-amino- 5-Cyano-2- [1- (6-methylpyridin-2-yl) ethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide was obtained.
White powder
¹ H-NMR (CDCl ₃ ) δ: 10.25 (1H, brs), 7.83 (2H, d, J = 7 Hz), 7.73 (2H, d, J = 6 Hz), 7.62 (1H, t, J = 6 Hz), 7.32 (1H, d, J = 6 Hz), 7.13 (1H, d, J = 6 Hz), 5.10 (1H, q, J = 6 Hz), 2.47 (3H, s), 2.09 (3H, s), 1.69 (3H, d, J = 6 Hz).

In the same manner as described in Example 2, using 1- (6-methylpyridin-2-yl) pentan-1-ol instead of 6-methyl-2-pyridinemethanol, N- (4- { 6-Amino-5-cyano-2- [1- (6-methylpyridin-2-yl) pentylsulfanyl] pyrimidin-4-yl} phenyl) acetamide was obtained.
White powder
¹ H-NMR (CDCl ₃ ) δ: 8.40 (1H, brs), 7.94 (2H, d, J = 6 Hz), 7.63 (2H, d, J = 6 Hz), 7.52 (1H, t, J = 6 Hz), 7.22 (1H, d, J = 6 Hz), 7.00 (1H, d, J = 6 Hz), 5.79 (1H, brs), 5.03 (1H, t, J = 6 Hz), 2.55 (3H, s), 2.21 (3H, s), 2.00-2.15 (2H, m), 1.20-1.45 (4H, m), 0.86 (3H, t, J = 6 Hz).

5.5 g of the compound obtained in Example 2 was suspended in a mixed solvent of 50 mL of ethanol and 50 mL of water, 50 mL of 5N hydrochloric acid was added to this suspension, and the resulting solution was heated and stirred at 80 ° C. for 5 hours. After cooling the reaction mixture, ethanol was distilled off under reduced pressure and neutralized by adding 5N aqueous sodium hydroxide solution under ice cooling. The precipitated crystals were collected by filtration, recrystallized with ethanol, and 2.3 g of 4-amino-6- (4-aminophenyl) -2- (6-methylpyridin-2-ylmethylsulfanyl) pyrimidine-5-carbohydrate. Nitrile was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 7.48-7.98 (2H, br s), 7.74 (2H, d, J = 8.7 Hz), 7.60 (1H, t, J = 7.8 Hz), 7.32 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 7.8 Hz), 6.61 (2H, d, J = 8.7 Hz), 5.90 (2H, s), 4.44 (2H, s), 2.45 (3H, s).

170 mg of the compound obtained in Example 8 and 0.2 mL of triethylamine were dissolved in 10 mL of acetonitrile, and 0.12 g of propionyl chloride was added dropwise to the solution, followed by stirring at room temperature overnight. The precipitated crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure to give 85 mg of N- {4- [6-amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl) pyrimidine -4-yl] phenyl} propionamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.16 (1H, s), 7.84 (2H, d, J = 8.7 Hz), 7.74 (2H, d, J = 8.7 Hz), 7.61 (1H, t, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 7.8 Hz), 4.45 (2H, s), 2.45 (3H, s), 2.37 (2H, q, J = 8.7Hz), 1.10 (3H, t, J = 7.5 Hz).

N- {4- [6-amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl) was prepared in the same manner as described in Example 9 using acryloyl chloride in place of propionyl chloride. ) Pyrimidin-4-yl] phenyl} acrylamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.43 (1H, s), 7.79-7.89 (4H, m), 7.61 (1H, t, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz ), 7.12 (1H, d, J = 7.8 Hz), 6.42-6.52 (1H, m), 6.31 (1H, dd, J = 16.8, 2.1 Hz), 5.81 (1H, dd, J = 9.9, 2.1 Hz) , 4.45 (2H, s), 2.45 (3H, s).

N- {4- [6-amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl)] was used in the same manner as described in Example 9 using butyryl chloride instead of propionyl chloride. Pyrimidin-4-yl] phenyl} butyramide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.17 (1H, s), 7.65-8.20 (2H, br s), 7.83 (2H, d, J = 8.7 Hz), 7.74 (2H, d, J = 8.7 Hz), 7.61 (1H, t, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 7.8 Hz), 4.45 (2H, s), 2.45 (3H, s), 2.33 (2H, t, J = 7.5Hz), 1.63 (3H, sext, J = 7.5Hz), 0.93 (3H, t, J = 7.5Hz).

N- {4- [6-amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl)] was used in the same manner as described in Example 9 using benzoyl chloride instead of propionyl chloride. Pyrimidin-4-yl] phenyl} benzamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.53 (1H, s), 7.80-8.01 (6H, m), 7.51-7.70 (4H, m), 7.35 (1H, d, J = 7.5 Hz), 7.13 (1H, d, J = 7.5Hz), 4.47 (2H, s), 2.46 (3H, s).

Using 6-methyl-2-pyridinemethanol, thiourea and the compound obtained in Reference Example 1, the same method as described in Example 2 was repeated to obtain {4- [6-amino-5-cyano-2 -(6-Methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} carbamic acid methyl ester was obtained.
Yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.01 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.61 (1H, t, J = 7.5 Hz), 7.60 (2H, d, J = 8.7 Hz), 7.33 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 4.45 (2H, s), 3.70 (3H, s), 2.45 (3H, s).

  The structures of the compounds obtained in Examples 1 to 13 are shown in Tables 6 to 7 below.

  10 g of the compound obtained in Reference Example 2, 9.8 g of the compound obtained in Reference Example 3, 3.52 g of sodium bicarbonate and 5.40 g of sodium iodide were added to 100 mL of DMF, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride-ethanol-triethylamine = 800: 40: 1) to obtain 1.67. g N- {4- [6-Amino-5-cyano-2- (6-morpholin-4-ylmethylpyridin-2-ylmethylsulfanyl) -2,3-dihydropyrimidin-4-yl] phenyl} acetamide Got.

  This compound (600 mg) was dissolved in 1,4-dioxane (12 mL), DDQ (290 mg) was added to the solution, and the mixture was heated to reflux for 2 hours. After the solvent was distilled off from the resulting reaction solution, water was added to the residue, and 1N hydrochloric acid was added to make the solution acidic. After the reaction solution was washed with ethyl acetate, 1N aqueous sodium hydroxide solution was added to the aqueous layer to make the solution basic, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 290 mg of N- {4- [6-amino-5-cyano-2- (6-morpholin-4-ylmethylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl ] Phenyl} acetamide was obtained.

The total amount thereof was dissolved in ethanol, and 0.61 mL of 1 mol / L hydrochloric acid ethanol solution was added to the resulting solution, followed by drying under reduced pressure to obtain the above-mentioned compound in hydrochloride form.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.82 (2H, d, J = 8.7 Hz), 7.72-7.67 (3H, m), 7.40 (1H, d, J = 7.8 Hz ), 7.31 (1H, d, J = 7.8 Hz), 4.47 (2H, s), 3.57 (4H, br t), 2.39 (4H, br t), 2.08 (3H, s).

  To a solution of 287 mg of the compound obtained in Reference Example 2 in 3 mL of DMF, 260 mg of the compound obtained in Reference Example 4, 100 mg of sodium bicarbonate and 150 mg of sodium iodide were added and stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Acetonitrile 1mL and NBS 7.3mg were added to the residue, and it heated and refluxed for 30 minutes. After allowing to cool, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give 35 mg of N- (4- {6-amino-5-cyano-2- [6- (2-morpholin-4-ylethyl) pyridin-2-ylmethylsulfanyl] pyrimidine-4 -Il} phenyl) acetamide was obtained.

The total amount was dissolved in ethanol, and 0.14 mL of a 1 mol / L hydrochloric acid ethanol solution was added to the resulting solution, followed by drying under reduced pressure to obtain 40 mg of the target compound in hydrochloride form.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.71 (2H, d, J = 8.7 Hz), 7.66 (1H, t, J = 7.2 Hz), 7.33 (1H, d, J = 7.2 Hz), 7.15 (1H, d, J = 7.2 Hz), 4.46 (2H, s), 3.55-3.52 (4H, m), 2.86 (2H, t, J = 7.2 Hz), 2.60 (2H, t, J = 7.2 Hz), 2.39 (4H, br t), 2.03 (3H, s).

  86 mg of thiourea and 290 mg of the compound obtained in Reference Example 5 were suspended in 50 mL of ethanol, and the resulting suspension was stirred at 60 ° C. for 1 hour. After allowing to cool, 240 mg of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 287 mg of sodium bicarbonate were added to this solution, and the mixture was heated to reflux for 5 hours. After allowing to cool, NBS 200 mg was further added and heated to reflux for 1 hour. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia = 300: 10: 1) to give 85 mg of N- (4- {6-amino-5-cyano-2- [6- (3-morpholine). -4-ylpropyl) pyridin-2-ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide was obtained.

The total amount was dissolved in ethanol, 0.38 mL of 1 mol / L hydrochloric acid ethanol solution was added to this solution, and then the solvent was distilled off to obtain 110 mg of the target compound in the form of hydrochloride.
Yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.71 (2H, d, J = 8.7 Hz), 7.61 (1H, t, J = 7.5 Hz), 7.32 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 4.40 (2H, s), 3.64-3.50 (4H, m), 2.70 (2H, t , J = 7.5 Hz), 2.40-2.24 (6H, m), 2.08 (3H, s), 2.49-2.45 (2H, m).

15 g of the compound obtained in Reference Example 6 and 3.8 g of thiourea were suspended in 200 mL of ethanol, and the suspension was stirred at 60 ° C. for 1 hour. 9.72 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide was added to the reaction mixture, and the mixture was heated to reflux overnight. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-methanol-aqueous ammonia = 300: 10: 1), and 10.3 g of 4- {6- [4- (4-acetylaminophenyl) -6-amino- 5-Cyanopyrimidin-2-ylsulfanylmethyl] -pyridin-2-ylmethyl} piperazine-1-carboxylic acid t-butyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.72-7.70 (3H, m), 7.40 (1H, d, J = 7.5 Hz ), 7.32 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 3.57 (2H, s), 2.50-2.35 (8H, m), 2.20 (3H, s), 1.38 (9H, s) .

123 mg of the compound obtained in Example 17 was placed in an eggplant type flask, and 0.35 mL of trifluoroacetic acid was added thereto under ice cooling. After the mixture was stirred at room temperature for 1 hour, trifluoroacetic acid was distilled off under reduced pressure. To the residue was added 6 mL of 0.1 mol / L hydrochloric acid ethanol solution, and the solvent was evaporated to dryness. The residual solid was recrystallized from ethanol to give 80 mg of N- {4- [6-amino-5-cyano-2- (6-piperazin-1-ylmethylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl ] Phenyl} acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.3 (1H, s), 9.42 (1H, br s), 7.89-7.81 (3H, m), 7.73 (2H, d, J = 8.7Hz), 7.63 ( 1H, d, J = 7.5Hz), 7.52 (1H, d, J = 7.5Hz), 4.55 (2H, s), 3.37-3.25 (10H, m), 2.03 (3H, s).

292 mg of the compound obtained in Example 18, 61 mg of benzoic acid and 0.2 mL of triethylamine were dissolved in 3 mL of DMF, and 80 mg of HOBt was added to the solution under ice-cooling and stirring. The mixture was stirred at the same temperature for 15 minutes, 115 mg of WSC was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was dried under reduced pressure, ice water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and dried under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 300: 10: 1) to give 261 mg of N- (4- {6-amino-2- [6- (4-benzoylpiperazine-1 -Ilmethyl) pyridin-2-ylmethylsulfanyl] -5-cyanopyrimidin-4-yl} phenyl) acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.72-7.70 (3H, m), 7.44-7.32 (7H, m), 4.48 (2H, s), 3.60 (2H, s), 2.08 (3H, s).

146 mg of the compound obtained in Example 18, 28 mg of benzaldehyde and 75 mg of triethylamine were dissolved in a mixture of 1 mL of DMF and 2 mL of methanol, and the resulting solution was stirred at room temperature overnight. Under ice-cooling, 30 mg of sodium cyanoborohydride was added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was evaporated to dryness, ice water was added to this, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then dried under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 600: 20: 1) to give 60 mg of N- (4- {6-amino-2- [6- (4-benzylpiperazine- 1-ylmethyl) pyridin-2-ylmethylsulfanyl] -5-cyanopyrimidin-4-yl} phenyl) acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 7.98 (2H, d, J = 8.7 Hz), 7.64 (2H, d, J = 8.7 Hz), 7.58 (1H, t, J = 7.5 Hz), 7.53- 7.50 (2H, m), 7.42-7.29 (5H, m), 4.54 (2H, s), 3.75 (2H, s), 2.61-2.48 (10H, m), 2.20 (3H, s).

Using (4-methylpiperazin-1-yl) acetic acid instead of benzoic acid in the same manner as described in Example 19, N- {4- [6-amino-5-cyano-2- (6- {4- [2- (4-Methylpiperazin-1-yl) acetyl] piperazin-1-ylmethyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.73-7.70 (3H, m), 7.40 (1H, d, J = 7.5 Hz ), 7.32 (1H, d, J = 7.5 Hz), 4.48 (2H, s), 3.59 (2H, s), 3.43 (2H, br t), 3.36-3.33 (4H, m), 3.08 (2H, s ), 2.49-2.27 (10H, m), 2.12 (3H, s), 2.08 (3H, s).

N- [4- (6-Amino-5-cyano-2- {6- [4- (4) was used in the same manner as in Example 19 except that p-methoxybenzoic acid was used instead of benzoic acid. -Methoxybenzoyl) piperazin-1-ylmethyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.97 (1H, d, J = 8.4 Hz), 7.83 (2H, d, J = 8.7 Hz), 7.73-7.68 (3H, m), 7.53 (1H, t, J = 7.2 Hz), 7.43-7.32 (3H, m), 6.96 (1H, d, J = 8.7 Hz), 4.47 (2H, s), 3.78 (3H, s), 3.62 (3H, s), 3.48-3.32 (2H, m), 2.49-2.45 (4H, m), 2.08 (3H, s).

N- [4- (6-Amino-5-cyano-2- {6- [4- () was used in the same manner as in Example 19 except that N, N-dimethylglycine was used instead of benzoic acid. 2-Dimethylaminoacetyl) piperazin-1-ylmethyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 9.0 Hz), 7.72-7.68 (3H, m), 7.42 (1H, d, J = 7.5 Hz ), 7.33 (1H, d, J = 7.5 Hz), 4.48 (2H, s), 3.59 (2H, s), 3.49-3.41 (4H, m), 3.15 (2H, br s), 2.48-2.42 (4H m), 2.21 (6H, s), 2.08 (3H, s).

N- [4- (6-Amino-5-cyano-2- {6- [4- (3) was used in the same manner as in Example 19 except that 1-piperidinepropionic acid was used in place of benzoic acid. -Piperidin-1-ylpropionyl) piperazin-1-ylmethyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.74-7.68 (3H, m), 7.43 (1H, t, J = 7.5 Hz), 7.33 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 3.60 (2H, s), 3.44-3.34 (4H, m), 2.51-2.50 (4H, m), 2.43-2.37 (4H, m), 2.09 (3H, s), 1.58 (4H, br s), 1.43 (2H, br t).

N- [4- (6-Amino-5-cyano-2- {6- [4- ( 2-Piperidin-1-ylacetyl) piperazin-1-ylmethyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
White powder
¹ H-NMR (CD ₃ OD) δ: 7.90-7.81 (3H, m), 7.73 (2H, d, J = 8.7 Hz), 7.69 (2H, d, J = 7.8 Hz), 7.43 (1H, t, J = 7.8 Hz), 4.64 (2H, s), 4.55 (2H, s), 4.42 (2H, s), 3.92 (1H, br s), 3.77-3.72 (3H, m), 3.58-3.51 (2H, m), 3.44-3.31 (2H, m), 3.29-3.14 (2H, m), 2.16 (3H, s), 2.10-2.06 (2H, m), 1.36-1.31 (2H, m).

  The structures of the compounds obtained in Examples 14 to 25 are shown in Tables 8 to 9 below.

571 mg of the compound obtained in Reference Example 7 and 180 mg of thiourea were dissolved in 20 mL of ethanol, and this solution was heated to reflux for 1 hour. After cooling, 500 mg of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 600 mg of sodium bicarbonate were added to the reaction mixture, and the mixture was heated to reflux for 4 hours. After cooling, 356 mg of NBS was added to the reaction mixture and heated to reflux for 1 hour. After cooling, 5 mL of saturated aqueous sodium hydrogen carbonate solution and 10 mL of water were further added, and the precipitated insoluble matter was collected by filtration, washed with water, and dried under reduced pressure, and N- (4- {6-amino-5-cyano-2- [6 380 mg of-(morpholin-4-carbonyl) pyridin-2-ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.86 (1H, t, J = 7.8 Hz), 7.79 (2H, d, J = 9.0 Hz), 7.70 (2H, d, J = 9.0 Hz), 7.62 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 4.53 (2H, s), 3.63 (4H, br t), 3.49-3.44 (2H, m), 2.08 (3H, s).

Using the compound obtained in Reference Example 8 instead of the compound obtained in Reference Example 7, in the same manner as in Example 26, 6- [4- (4-acetylaminophenyl) -6-amino- 5-Cyanopyrimidin-2-ylsulfanylmethyl] pyridine-2-carboxylic acid t-butyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 7.82-7.72 (7H, m), 4.55 (2H, s), 2.08 (3H, S), 1.54 (9H, s).

Using the compound obtained in Reference Example 9 in place of the compound obtained in Reference Example 7, and using the same method as described in Example 26, 4- {6- [4- (4-acetylaminophenyl) -6 -Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine-2-carbonyl} piperazine-1-carboxylic acid t-butyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.89 (1H, t, J = 7.8 Hz), 7.83 (2H, d, J = 8.7 Hz), 7.75 (2H, d, J = 8.7 Hz), 7.63 (1H, d, J = 7.8 Hz), 7.47 (1H, d, J = 7.8 Hz), 4.53 (2H, s), 3.60-3.56 (2H, br), 3.45-3.31 (6H , br), 2.09 (3H, s), 1.40 (12H, s).

To 600 mg of the compound obtained in Example 28, 2 mL of TFA was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. Excess TFA was distilled off under reduced pressure, and 20 mL of 0.1 mol / L hydrochloric acid ethanol solution was added to the residue and stirred. The precipitated crystals were collected by filtration, and 80 mg of N- (4- {6-amino-5-cyano- 2- [6- (Piperazin-1-carbonyl) pyridin-2-ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 9.16 (2H, br), 7.90 (1H, t, J = 7.8 Hz), 7.80 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.69 (1H, d, J = 7.8 Hz), 7.55 (1H, d, J = 7.8 Hz), 4.54 (2H, s), 3.86 (2H, br), 3.70 (2H, br), 3.20-3.10 (4H, br), 2.09 (3H, s).

  The structures of the compounds obtained in Examples 26 to 29 are shown in Table 10 below.

Dissolve 1 g of (6-hydroxymethylpyridin-2-ylmethyl) carbamic acid t-butyl ester and 1.1 mL of diisopropylethylamine in 20 mL of dichloromethane, add 0.33 mL of methanesulfonyl chloride dropwise at room temperature, and mix the mixture. Stir at warm for 1 hour. Water was added to the reaction mixture, and the organic layer was washed twice with water and once with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was dissolved in 25 mL of ethanol together with 0.32 g of thiourea, and the resulting solution was heated to reflux for 1 hour. NBS 0.4g was added to the reaction mixture, and it heated and refluxed for 5 minutes, and stood to cool, Then, the solvent was distilled off. The residue was dissolved in chloroform, washed twice with water and once with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride-methanol-aqueous ammonia = 90: 10: 1). The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 0.97 g of {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine- 2-ylmethyl} carbamic acid t-butyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.25 (1H, s), 8.25-7.49 (2H, br s), 7.98 (1H, t, J = 7.5 Hz), 7.83 (2H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.7 Hz), 7.64 (1H, d, J = 7.5 Hz), 7.53 (1H, br s), 7.33 (1H, d, J = 7.5 Hz), 4.54 (2H , s), 4.29 (2H, d, J = 5.7 Hz), 2.09 (3H, s), 1.40 (9H, s).

  1 mL of trifluoroacetic acid was added to 0.2 g of the compound obtained in Example 30, and the mixture was stirred at room temperature for 30 minutes, and then trifluoroacetic acid was distilled off from the mixture. To the residue, 2 mL of triethylamine was added and stirred, and then 0.19 g of WSC, 0.14 g of HOBt and 41 mg of N, N-dimethylglycine were added, and the resulting mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with ethanol and dried, and 76 mg of N- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidine- 2-ylsulfanylmethyl] pyridin-2-ylmethyl} -2-dimethylaminoacetamide was obtained.

The total amount of this product was dissolved in 2 mL of ethanol, and 1 mL of a 1 mol / L hydrochloric acid ethanol solution was added to the resulting solution, and then ethanol was distilled off under reduced pressure to obtain the target compound in the form of hydrochloride.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 8.36 (1H, t, J = 6.0 Hz), 8.25-7.65 (2H, br s), 7.85 (2H, d, J = 8.7 Hz), 7.72-7.66 (3H, m), 7.41 (1H, d, J = 7.5 Hz), 7.14 (1H, d, J = 7.5 Hz), 4.48 (2H, s), 4.38 (2H, d, J = 6.0 Hz), 2.94 (2H, s), 2.24 (6H, s), 2.09 (3H, s).

To 0.3 g of the compound obtained in Example 30, 2 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, trifluoroacetic acid was distilled off under reduced pressure from the reaction mixture, the residue was dissolved in 2 mL of acetonitrile, 4 mL of 28% aqueous ammonia was added to the resulting solution, and the precipitated crystals were collected by filtration, and 0.2 g of N- { 4- [6-Amino-2- (6-aminomethylpyridin-2-ylmethylsulfanyl) -5-cyanopyrimidin-4-yl] phenyl} acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.25 (1H, s), 8.25-7.65 (2H, br s), 7.84 (2H, d, J = 8.7 Hz), 7.75-7.65 (3H, m), 7.29-7.40 (2H, m), 4.47 (2H, s), 3.78 (2H, s), 2.09 (3H, s).

  0.2 g of the compound obtained in Example 32 and 0.5 mL of triethylamine were dissolved in 2 mL of DMF, 0.1 g of 4-pyrrolidin-1-ylbutyric acid hydrochloride, 0.07 g of HOBt and 0.1 g of WSC were added to the solution, and the mixture was stirred at room temperature. At rt overnight. Water was added to the reaction solution, the precipitated crystals were collected by filtration, and the resulting crude crystals were recrystallized from ethanol to obtain 43 mg of N- {6- [4- (4-acetylaminophenyl) -6-amino- 5-Cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-ylmethyl} -4-pyrrolidin-1-ylbutyramide was obtained.

The total amount of this product was dissolved in 2 mL of ethanol, and 1 mL of a 1 mol / L hydrochloric acid ethanol solution was added to the resulting solution, and then ethanol was distilled off under reduced pressure to obtain the hydrochloride of the target compound.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 8.40 (1H, t, J = 6.0 Hz), 8.25-7.65 (2H, br s), 7.85 (1H, d, J = 8.7 Hz), 7.74-7.66 (3H, m), 7.41 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 4.31 (2H, d, J = 6.0 Hz), 2.32-2.38 (6H, m), 2.20 (2H, t, J = 7.2 Hz), 2.09 (3H, s), 1.75-1.57 (6H, m).

  (6-Hydroxymethylpyridin-2-ylmethyl) -methylcarbamic acid t-butyl ester (0.76 g) and diisopropylethylamine (0.78 ml) were dissolved in methylene chloride (10 ml). . Water was added to the reaction mixture, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained oil was dissolved in 20 ml of ethanol, 0.23 g of thiourea was added to this solution, and the mixture was heated to reflux for 1 hour. The reaction mixture was allowed to cool, the solvent was evaporated under reduced pressure, and the residue was washed with diethyl ether to obtain 0.9 g of a light brown oil.

The total amount of this product and 0.63 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide were dissolved in 20 mL of ethanol, and the resulting solution was heated to reflux for 2 hours. NBS 0.32 g was added to the reaction mixture, and the mixture was further heated under reflux for 5 minutes. After standing to cool, the solvent was distilled off under reduced pressure. The residue was dissolved in chloroform, and the resulting liquid was washed twice with water and once with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was purified by silica gel column chromatography (methylene chloride-methanol-aqueous ammonia = 90: 10: 1). The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 0.51 g of {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine- 2-ylmethyl} methylcarbamic acid t-butyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 7.84 (2H, d, J = 8.4 Hz), 7.75-7.69 (3H, m), 7.43 (1H, d, J = 7.5 Hz ), 7.05 (1H, d, J = 7.5 Hz), 4.48 (3H, s), 4.43 (2H, s), 2.85 (3H, s) 2.09 (3H, s), 1.51-1.25 (9H, m).

Using the compound obtained in Example 34 instead of the compound obtained in Example 30 as a raw material, N- {4- [6-amino-5-cyano-2- (6 -Methylaminomethylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 7.65-8.25 (2H, br s), 7.84 (2H, d, J = 8.7 Hz), 7.72-7.66 (3H, m), 7.41 (1H, d, J = 7.8 Hz), 7.30 (1H, d, J = 7.8 Hz), 4.48 (2H, s), 3.74 (2H, s), 2.31 (3H, s), 2.09 (3H, s ).

Using the compound obtained in Example 35 instead of the compound obtained in Example 32 and according to the method described in Example 33, N- {6- [4- (4-acetylaminophenyl) -6-amino- 5-Cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-ylmethyl} -N-methyl-4-pyrrolidin-1-ylbutyramide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 8.22-7.66 (2H, br s), 7.86-7.65 (5H, m), 7.47-7.39 (1H, m), 7.13-7.01 (1H, m), 4.71-4.42 (4H, m), 3.05-2.78 (3H, m), 2.45-2.20 (8H, m), 2.09 (3H, s), 1.75-1.55 (6H, m).

0.5 g of the compound obtained in Example 32 and 0.3 mL of triethylamine were dissolved in 5 mL of DMSO, and 0.17 g of 3-bromopropionyl chloride was added to the obtained liquid under ice cooling, followed by stirring for 30 minutes. The reaction mixture was diluted with chloroform, washed twice with water and once with saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The crude crystals obtained by distilling off the solvent were washed with diethyl ether, and 0.12 g of N- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-yl Sulfanylmethyl] pyridin-2-ylmethyl} acrylamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.29 (1H, s), 8.73-8.65 (1H, m), 8.25-7.65 (2H, br s), 7.84 (2H, d, J = 9 Hz), 7.81-7.70 (3H, m), 7.50-7.45 (1H, m), 7.23-7.11 (1H, m), 6.20-5.79 (3H, m), 4.51-4.32 (4H, m), 2.10 (3H, s ).

0.11 g of the compound obtained in Example 37 and 0.1 g of 4-piperidinopiperidine were dissolved in 2 mL of DMSO, and the resulting solution was stirred overnight at room temperature. Chloroform and water were added to the reaction solution, the organic layer was washed twice with water and then once with saturated brine, and the organic layer was dried over magnesium sulfate. After the solvent was distilled off, the obtained residue was purified by silica gel column chromatography (methylene chloride-methanol-28% aqueous ammonia = 90: 10: 1) to give 50 mg of N- {6- [4- (4- Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-} ylmethyl} -3- [1,4 ′] bipiperidinyl-1′-ylpropionamide was obtained. This was converted to the hydrochloride salt according to the method described in Example 31. The physical properties of the obtained hydrochloride are shown below.
Pale yellow oil
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.71 (2H, d, J = 8.7 Hz), 7.66 (1H, t, J = 7.2 Hz), 7.33 (1H, d, J = 7.2 Hz), 7.15 (1H, d, J = 7.2 Hz), 4.46 (2H, s), 3.55-3.52 (4H, m), 2.86 (2H, t, J = 7.2 Hz), 2.60 (2H, t, J = 7.2 Hz), 2.39 (4H, br t), 2.03 (3H, s).

1 mL of trifluoroacetic acid was added to 0.2 g of the compound obtained in Example 30, and the mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was dried under reduced pressure. The residue was dissolved in 5 mL of acetonitrile, and 2 mL of triethylamine was added to the resulting solution and stirred at room temperature. Next, 63 mg of 4-methyl-1-piperazinecarbonyl chloride hydrochloride was added and stirred overnight at room temperature. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with ethanol, dried, and 35 mg of 4-methylpiperazine-1-carboxylic acid {6- [4- (4-acetylaminophenyl) -6- Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-ylmethyl} amide was obtained. This was converted to the hydrochloride salt according to the method described in Example 31. The physical properties of the obtained hydrochloride are as follows.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 8.25-7.65 (2H, br s), 7.86 (2H, d, J = 8.7 Hz), 7.74-7.65 (3H, m), 7.38 (1H, d, J = 7.5 Hz), 7.17-7.10 (2H, m), 4.47 (2H, s), 4.31 (2H, d, J = 6.0 Hz), 3.35-3.30 (4H, m), 2.31 -2.24 (4H, m), 2.37 (3H, s), 2.10 (3H, s).

To a suspension of 0.1 g of the compound obtained in Example 32 in 5 mL of DMSO was added 0.25 mL of diisopropylethylamine, and 0.04 mL of 1-propanesulfonyl chloride was further added dropwise to the mixture with stirring. 30 minutes after the dropwise addition, water was added to the reaction mixture, and the precipitated crystals were collected by filtration, dried under reduced pressure, and 80 mg of N- [4- (6-amino-5-cyano-2- {6-[(propane- 1-sulfonylamino) methyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 7.65-8.20 (5H, m), 7.46 (1H, d, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz ), 4.48 (2H, s), 4.22 (2H, d, J = 6.3 Hz), 2.94-3.01 (2H, m), 2.09 (3H, s), 1.55-1.70 (2H, m), 0.89 (3H, t, J = 7.5 Hz).

0.25 mL of diisopropylethylamine was added to a suspension of 0.1 g of the compound obtained in Example 35 in 5 mL of acetonitrile, and further 0.04 mL of 1-propanesulfonyl chloride was added dropwise to the mixture with stirring. One hour after the dropwise addition, water was added to the reaction mixture, and the precipitated crystals were collected by filtration, dried under reduced pressure, and 80 mg of N- {4- [6-amino-5-cyano-2- (6-{[methyl ( Propane-1-sulfonyl) amino] methyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 7.65-8.20 (5H, m), 7.49 (1H, d, J = 7.8 Hz), 7.27 (1H, d, J = 7.8 Hz ), 4.50 (2H, s), 4.40 (2H, s), 2.77-3.32 (2H, m), 2.79 (3H, s), 2.09 (3H, s), 1.61-1.76 (3H, m), 0.96 ( 3H, t, J = 7.2 Hz).

  The structures of the compounds obtained in Examples 30 to 41 are shown in Tables 11 to 12 below.

Thiorurea (5.33 g) was dissolved in ethanol (70 mL) at 60 ° C., and the resulting solution was added with 19.21 g of the compound obtained in Reference Example 10 in 50 mL of ethanol, and the mixture was stirred at the same temperature for 2 hours. After cooling, 14.7 g of sodium bicarbonate was added to the reaction mixture, and the mixture was stirred at room temperature for 10 minutes. Furthermore, 14.8 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 50 mL of ethanol were added to the mixture, and the mixture was heated to reflux overnight. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was dissolved in 200 mL of ethanol, and 2 g of NBS was added a total of 4 times every hour while heating under reflux. After cooling, the reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated to dryness. The residue was purified by silica gel column chromatography (chloroform-methanol = 10: 1), recrystallized from acetone-IPE, and 16.19 g of 3- {6- [4- (4-acetylaminophenyl) -6- Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} propionic acid t-butyl ester was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 7.83 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.63 (1H, t, J = 7.5 Hz), 7.35 ( 1H, d, J = 7.5 Hz), 7.14 (1H, d, J = 7.5 Hz), 4.45 (2H, s), 2.94 (2H, t, J = 7.5 Hz), 2.61 (2H, t, J = 7.5 Hz), 2.09 (3H, s), 1.34 (9H, s).

3 g of the compound obtained in Reference Example 11 was dissolved in 50 mL of dichloromethane, 4 mL of diisopropylethylamine was added to the obtained liquid, 1.3 mL of methanesulfonyl chloride was further added dropwise under ice cooling, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained brown oil was dissolved in 50 mL of ethanol, 1.0 g of thiourea was added to the solution, and the mixture was heated to reflux for 1 hour. After allowing the reaction solution to cool, 2.5 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide, 5 mL of diisopropylethylamine and 1 drop of DBU were added, and the mixture was stirred at room temperature overnight. After distilling off the solvent from the reaction mixture under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, and 1.8 g of NBS was added to the resulting solution under ice-cooling and stirring, followed by stirring for 30 minutes. Water was added to the reaction mixture, and the organic layer was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained white oil was crystallized by adding 2-propanol and recrystallized from 2-propanol to give 2.3 g of 3- {6- [4- (4-acetylaminophenyl) -6-amino- 5-Cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} propionic acid ethyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 7.26-8.20 (2H, br s) 7.83 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz ), 7.63 (1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz) 7.15 (1H, d, J = 7.8 Hz) 4.45 (2H, s), 4.03 (2H, q, J = 7.2 Hz), 2.98 (2H, t, J = 7.2 Hz), 2.70 (2H, t, J = 7.2 Hz), 2.09 (3H, s), 1.14 (3H, t, J = 7.2 Hz).

Using the compound obtained in Reference Example 12 instead of the compound obtained in Reference Example 11, according to the method described in Example 43, 3- {6- [4- (4-acetylaminophenyl) -6-amino- 5-Cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} propionic acid methyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 8.20-7.60 (2H, br s), 7.83 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.63 (1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz), 7.15 (1H, d, J = 7.8 Hz), 4.45 (2H, s), 3.57 (3H, s), 2.96 (2H, t, J = 7.2 Hz), 2.74 (2H, t, J = 7.2 Hz), 2.09 (3H, s).

8.21 g of the compound obtained in Example 42 was ice-cooled, 30 mL of TFA was added thereto, and the mixture was stirred at room temperature for 1.5 hours. After distilling off TFA under reduced pressure, 100 mL of chloroform was added to the reaction solution and distilled again under reduced pressure. The resulting residue was dissolved in acetone, and 18 mL of 1N hydrochloric acid was added thereto and dried under reduced pressure. The residue was dispersed in acetone and filtered to give 6.82 g of 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine-2. -Il} propionate hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.38 (1H, t, J = 7.8 Hz), 8.05 (1H, d, J = 7.8 Hz), 7.82 (2H, d, J = 9.0 Hz), 7.81 (1H , d, J = 7.8 Hz), 7.72 (2H, d, J = 9.0 Hz), 4.69 (2H, s), 3.15 (2H, t, J = 6.9 Hz), 2.84 (2H, t, J = 6.9 Hz ), 2.16 (3H, s).

  100 mg of the compound obtained in Example 45 was suspended in 2 mL of methylene chloride, 34 μL of N-methylpiperazine, 79 mg of WSC and 72 μL of diisopropylethylamine were added to the resulting suspension, and the mixture was stirred overnight at room temperature. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol-28% aqueous ammonia = 100: 10: 1), and 95 mg of N- [4- (6-amino-5-cyano-2- {6- [ 3- (4-Methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide was obtained.

69 mg of this compound was dissolved in methanol, 0.29 mL of 1N hydrochloric acid was added to the resulting solution, and the mixture was dried under reduced pressure. The residue was recrystallized from methanol-IPE to obtain 67 mg of hydrochloride of the above compound. The physical properties of this hydrochloride are shown below.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.39 (1H, t, J = 7.8 Hz), 8.04 (1H, d, J = 7.8 Hz), 7.83 (1H, d, J = 7.8 Hz), 7.82 (2H , d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 4.72 (2H, s), 3.65-3.40 (4H, m), 3.26-2.99 (8H, m), 2.91 (3H, s), 2.16 (3H, s).

Using the compound obtained in Reference Example 14 instead of the compound obtained in Reference Example 10, in the same manner as in Example 42, 3- {6- [4- (4-acetylaminophenyl) -6 -Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} acrylic acid t-butyl ester was obtained.
Light brown powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.22 (1H, s), 7.82 (2H, d, J = 8.7 Hz), 7.79 (1H, t, J = 7.5 Hz), 7.70 (2H, d, J = 8.7 Hz), 7.60 (1H, d, J = 7.5 Hz), 7.55 (1H, d, J = 7.5 Hz), 7.53 (1H, d, J = 15.9 Hz), 6.78 (1H, d, J = 15.9 Hz), 4.53 (2H, s), 2.08 (3H, s), 1.48 (9H, s).

  In an eggplant-shaped flask, 251 mg of the compound obtained in Example 47 was placed, and after ice cooling, 0.5 mL of TFA was further added, and the mixture was stirred at room temperature for 1 hour. TFA was distilled off from the reaction mixture under reduced pressure, 5 mL of acetonitrile was added to the oily residue, and 5 mL of triethylamine was further added dropwise with stirring under ice cooling. To this was further added 50 mg of N-methylpiperazine and 455 mg of BOP reagent, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia = 200: 10: 1) to give 40 mg of N- [4- (6-amino-5-cyano-2- { 6- [3- (4-Methylpiperazin-1-yl) -3-oxopropenyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide was obtained.

The total amount of this product was dissolved in ethanol, 0.15 mL of 1 mol / L hydrochloric acid ethanol solution was added to the obtained liquid, and the solvent was distilled off to obtain 48 mg of the above compound in the form of hydrochloride. The physical properties of this hydrochloride are shown below.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.82 (2H, d, J = 9.0 Hz), 7.76 (1H, d, J = 7.8 Hz), 7.70 (2H, d, J = 9.0 Hz), 7.61 (1H, d, J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.46 (2H, s), 4.53 (2H, s), 3.57 (4H, br t) , 2.31 (4H, br t), 2.19 (3H, s), 2.08 (3H, s).

Using the compound obtained in Reference Example 13 instead of the compound obtained in Reference Example 11, in the same manner as in Example 43, 3- {6- [4- (4-acetylaminophenyl) -6 -Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -2-methylpropionic acid ethyl ester was obtained.
Pale yellow powder
¹ H-NMR (CDCl ₃ ) δ: 7.99 (2H, d, J = 9.0 Hz), 7.64 (2H, d, J = 9.0 Hz), 7.50 (1H, t, J = 7.5 Hz), 7.28 (1H, d, J = 7.5 Hz), 6.99 (1H, d, J = 7.5 Hz), 5.82 (2H, br s), 4.52 (1H, d, J = 14.4 Hz), 4.44 (1H, d, J = 14.4 Hz ), 4.13 (2H, q, J = 7.2 Hz), 3.17 (1H, dd, J = 13.8, 7.8 Hz), 3.08-3.00 (1H, m), 2.87 (1H, dd, J = 13.8, 6.0 Hz) , 2.21 (3H, s), 1.26-1.12 (6H, m).

1.13 g of the compound obtained in Example 49 was dissolved in 30 mL of ethanol, 7.5 mL of 1N aqueous sodium hydroxide solution was added to the resulting solution, and the mixture was stirred at room temperature overnight. The solvent was removed from the reaction mixture under reduced pressure, and 2% citric acid aqueous solution was added to the residue to neutralize and disperse. The insoluble material was collected by filtration and purified by silica gel column chromatography (methylene chloride-methanol = 10: 1). To obtain 597 mg of 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -2-methylpropionic acid. It was.
Colorless powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 7.83 (2H, d, J = 9.0 Hz), 7.71 (2H, d, J = 9.0 Hz), 7.63 (1H, t, J = 7.5 Hz), 7.36 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 3.05 (1H, dd, J = 13.8, 6.9 Hz), 2.86 (1H, sext, J = 6.9 Hz), 2.71 (1H, dd, J = 13.8, 7.2 Hz), 2.09 (3H, s), 1.04 (3H, d, J = 6.9 Hz).

Using the compound obtained in Example 50 instead of the compound obtained in Example 45 and in the same manner as in Example 46, N- [4- (6-amino-5-cyano-2- { 6- [2-Methyl-3- (4-methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 7.84 (2H, d, J = 9.0 Hz), 7.72 (2H, d, J = 9.0 Hz), 7.60 (1H, t, J = 7.5 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.04 (1H, d, J = 7.5 Hz), 4.49 (1H, d, J = 13.8 Hz), 4.42 (1H, d, J = 13.8 Hz), 3.35-3.25 (5H, m), 2.97 (1H, dd, J = 17.1, 8.4 Hz), 2.69 (1H, dd, J = 17.1, 6.0 Hz), 2.54-1.91 (4H, m), 2.09 (6H, s), 1.04 (3H, d, J = 6.0 Hz).

540 mg of the compound obtained in Reference Example 15 and 244 mg of diisopropylethylamine were added to 9 mL of dichloromethane, and the mixture was stirred for 10 minutes under ice-cooling. Then, 0.16 mL of methanesulfonic acid chloride was added dropwise to the mixture and stirred at room temperature for 1 hour. The obtained mesylate solution was added dropwise at 60 ° C. to 2 mL of ethanol in 142 mg of thiourea, and the mixture was stirred at the same temperature for 1 hour. After the solvent was distilled off from the reaction mixture, 9 mL of ethanol, 396 mg of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 473 mg of sodium hydrogen carbonate were added to the residue, and the mixture was heated to reflux for 2 hours. After allowing the reaction liquid to cool, 270 mg of NBS was added thereto, and the mixture was heated to reflux for 30 minutes. After evaporating the solvent from the reaction mixture under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 600: 20: 1), and the purified product was recrystallized from ethanol to give 190 mg of N- [4- (6-amino-5-cyano -2- {6- [5- (4-Methylpiperazin-1-yl) -5-oxopent-1-ynyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.73-7.67 (3H, m), 7.49 (1H, d, J = 7.5 Hz ), 7.30 (1H, d, J = 7.5 Hz), 4.45 (2H, s), 3.38-3.32 (4H, m), 2.62 (4H, s), 2.29-2.21 (4H, m), 2.14 (3H, s), 2.09 (3H, s).

To 28 mL of ethanol were added 2.28 g of the compound obtained in Reference Example 16 and 545 mg of thiourea, and the mixture was stirred at 60 ° C. for 1.5 hours. After allowing to cool, 1.40 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 1.46 g of triethylamine were added to the mixture, and the mixture was stirred at 60 ° C. for 4 hours. The resulting reaction solution was ice-cooled, 27 mg of NBS8 was added thereto, and the mixture was stirred at the same temperature for 30 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride-ethanol = 30: 1) to obtain 1.86 g of 5- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidine-2 -Iylsulfanylmethyl] pyridin-2-yl} pentanoic acid t-butyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.4 Hz), 7.70 (2H, d, J = 8.4 Hz), 7.62 (1H, t, J = 7.5 Hz), 7.34 (1H, d, J = 7.5 Hz), 7.10 (1H, d, J = 7.5 Hz), 4.45 (2H, s), 2.69 (2H, t, J = 7.5 Hz), 2.19 ( 2H, t, J = 7.5 Hz), 2.08 (3H, s), 1.66-1.47 (4H, m), 1.37 (9H, s).

1.06 g of the compound obtained in Example 53 was ice-cooled, 2 mL of TFA was added dropwise thereto, and the mixture was stirred at room temperature for 1.5 hours. Excess TFA was distilled off under reduced pressure, the residue was dissolved in 20 mL of DMF, and the solution was neutralized by adding 3 mL of triethylamine under ice cooling, and further 1.8 g of HOBt was added and stirred for 15 minutes. To the reaction mixture was added 200 mg N-methylpiperazine and 764 mg WSC and the mixture was stirred at room temperature overnight. The obtained reaction mixture was dried under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (methylene chloride-methanol-triethylamine = 300: 10: 1) to give 1.0 g of N- [4- (6-amino-5-cyano-2- {6- [5- (4-Methylpiperazin-1-yl) -5-oxopentyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide was obtained.
White powder
¹ H-NMR (CDCl ₃ ) δ: 8.34 (1H, s), 7.90 (2H, d, J = 8.4 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.52 (1H, t, J = 7.5 Hz), 7.31 (1H, d, J = 7.5 Hz), 7.01 (1H, d, J = 7.5 Hz), 5.71 (2H, s), 4.50 (2H, s), 3.62 (2H, t, J = 5.1 Hz), 3.50 (2H, t, J = 5.1 Hz), 2.82 (2H, t, J = 7.5 Hz), 2.44-2.34 (6H, m), 2.30 (3H, s), 2.20 (3H, s), 1.86-1.73 (4H, m).

N- {4- [6-amino-5-cyano-2- (6) was prepared in the same manner as described in Example 54, using 1- (2-diethylaminoethyl) piperazine instead of N-methylpiperazine. -{5- [4- (2-Diethylaminoethyl) piperazin-1-yl] -5-oxopentyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, t, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.64 (1H, t, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.12 (1H, d, J = 7.8 Hz), 4.46 (2H, s), 2.70 (2H, t, J = 7.5 Hz), 2.31- 2.26 (8H, m), 2.09 (3H, s), 1.65-1.63 (2H, m), 1.52-1.49 (2H, m), 0.97-0.90 (6H, m).

1 g of the compound obtained in Example 46 was suspended in a mixed solvent of 10 mL of ethanol and 10 mL of water, 10 mL of 5N hydrochloric acid was added to the suspension, and the mixture was heated and stirred at 60 ° C. for 4 hours. Ethanol was distilled off from the reaction mixture under reduced pressure, and the resulting mixture was neutralized by adding 5N aqueous sodium hydroxide solution under ice cooling. The precipitated crystals were collected by filtration, washed with diethyl ether and dried under reduced pressure to obtain 0.85 g of 4-amino-6- (4-aminophenyl) -2- {6- [3- (4-methylpiperazine-1 -Iyl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidine-5-carbonitrile was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 7.73 (2H, d, J = 8.7 Hz), 7.80-7.55 (2H, br s), 7.61 (1H, t, J = 7.8 Hz), 7.33 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz), 6.61 (2H, d, J = 8.7 Hz), 5.90 (2H, s), 4.45 (2H, s), 3.40-3.34 ( 4H, m), 2.94 (2H, t, J = 7.2 Hz), 2.70 (2H, t, J = 7.2 Hz), 2.25-2.19 (4H, m), 2.12 (3H, s).

150 mg of the compound obtained in Example 56 and 0.5 mL of triethylamine were dissolved in 10 mL of acetonitrile, and 0.1 g of propionyl chloride was added dropwise to the mixture, followed by stirring at room temperature for 30 minutes. After the solvent was distilled off, the residue was dissolved in chloroform, water was added to the solution, and the resulting organic layer was washed twice with water and then once with saturated brine, and dried over magnesium sulfate. After evaporating the solvent under reduced pressure, the obtained oil was purified by silica gel column chromatography (methylene chloride-methanol-aqueous ammonia = 90: 10: 1) to give 50 mg of N- [4- (6-amino-5 -Cyano-2- {6- [3- (4-methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] propionamide was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.16 (1H, s), 8.20-7.64 (2H, br s), 7.84 (2H, d, J = 8.7 Hz), 7.74 (2H, d, J = 8.7 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz) 7.14 (1H, d, J = 7.8 Hz), 4.46 (2H, s), 3.42-3.35 (4H , m), 2.94 (2H, t, J = 7.2 Hz), 2.70 (2H, t, J = 7.2 Hz), 2.37 (2H, q, J = 7.5 Hz), 2.20-2.16 (4H, m), 2.12 (3H, s), 1.10 (3H, t, J = 7.5 Hz).

In Example 57, N- [4- (6-amino-5-cyano-2- {6- [3- (4-methylpiperazin-1-yl) was similarly obtained using butyryl chloride instead of propionyl chloride. ) -3-Oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] butyramide.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.73 (2H, d, J = 8.7 Hz), 7.62 (1H, t, J = 7.2 Hz), 7.34 (1H, d, J = 7.2 Hz), 7.14 (1H, d, J = 7.2 Hz), 4.46 (2H, s), 3.40-3.35 (4H, m), 2.94 (2H, t , J = 7.5 Hz), 2.70 (2H, t, J = 7.5 Hz), 2.20-2.16 (4H, m), 2.12 (3H, s), 1.63 (2H, sext, J = 7.5 Hz), 0.93 (3H , t, J = 7.5 Hz).

[2- (3- {6- [4- (4-acetylaminophenyl) was prepared in the same manner as described in Example 46, using N- (tert-butoxycarbonyl) ethylenediamine instead of N-methylpiperazine. ) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} propionylamino) ethyl] carbamic acid t-butyl ester was obtained.
Colorless powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 7.88 (1H, br t, J = 7.5 Hz), 7.83 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.62 (1H, t, J = 7.5 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 6.77 (1H, br t, J = 7.5 Hz), 4.46 (2H, s), 3.05 (2H, q, J = 7.5 Hz), 2.98-2.90 (4H, m), 2.46 (2H, t, J = 7.5 Hz), 2.09 (3H, s ).

To 100 mg of the compound obtained in Example 59, 1 mL of TFA was added under ice cooling, and the mixture was stirred for 30 minutes. The solid obtained by drying the reaction solution under reduced pressure was dissolved in 10 mL of ethanol, and 0.37 mL of 1N hydrochloric acid was added to the solution, followed by drying under reduced pressure. The obtained solid was recrystallized from methanol-IPE to give 90 mg of 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine-2. -Il} -N- (2-aminoethyl) propionamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 8.12 (1H, br t, J = 7.5 Hz), 7.85 (2H, br s), 7.82 (2H, d, J = 8.7 Hz ), 7.72 (2H, d, J = 8.7 Hz), 7.57 (1H, br d, J = 7.5 Hz), 7.34 (1H, br d, J = 7.5 Hz), 4.56 (2H, s), 3.29 (2H , q, J = 6.0 Hz), 3.07 (2H, t, J = 7.5 Hz), 2.85 (2H, q, J = 6.0 Hz), 2.59 (2H, t, J = 7.5 Hz), 2.09 (3H, s ).

  200 mg of the compound obtained in Example 45 was dissolved in 3 mL of DMF, 54 mg of N, N-dimethylethylenediamine, 365 mg of BOP and 172 μL of triethylamine were added to the resulting solution, and the mixture was stirred at room temperature overnight. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol-aqueous ammonia = 50: 10: 1).

187 mg of the free form compound obtained above was dissolved in methanol, 0.721 mL of 1N hydrochloric acid was added to the solution and dried under reduced pressure, and the resulting solid was recrystallized from methanol-acetone-IPE to give 186 mg of 3 -{6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl) propionamide hydrochloride Got. The physical properties of this hydrochloride are shown below.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.38 (1H, t, J = 7.8 Hz), 8.05 (1H, d, J = 7.8 Hz), 7.83 (2H, d, J = 9.0 Hz), 7.82 (1H , d, J = 7.8 Hz), 7.72 (2H, d, J = 9.0 Hz), 4.73 (2H, s), 3.53 (2H, t, J = 6.0 Hz), 3.27-3.22 (4H, m), 2.90 (6H, s), 2.82 (2H, t, J = 6.0 Hz), 2.16 (3H, s).

3- {6- [4- (4-acetylaminophenyl)-in the same manner as in Example 61, using N, N, N′-trimethylethylenediamine instead of N, N-dimethylethylenediamine. 6-Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl) -N-methylpropionamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.37 (1H, t, J = 8.1 Hz), 8.03 (1H, d, J = 8.1 Hz), 7.84 (1H, d, J = 8.1 Hz), 7.83 (2H , d, J = 9.0 Hz), 7.72 (2H, d, J = 9.0 Hz), 4.73 (2H, s), 3.72 (2H, t, J = 5.4 Hz), 3.32-3.21 (4H, m), 3.07 (3H, s), 3.02 (2H, t, J = 5.4 Hz), 2.92 (6H, s), 2.16 (3H, s).

In the same manner as in Example 61, except that 39 μL of 3-dimethylaminopropylamine was used instead of N, N-dimethylethylenediamine, 3- {6- [4- (4-acetylaminophenyl) -6 -Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminopropyl) propionamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.38 (1H, t, J = 7.8 Hz), 8.05 (1H, d, J = 7.8 Hz), 7.83 (2H, d, J = 9.0 Hz), 7.80 (1H , d, J = 7.8 Hz), 7.72 (2H, d, J = 9.0 Hz), 4.73 (2H, s), 3.23 (2H, t, J = 6.9 Hz), 3.10 (2H, t, J = 6.9 Hz ), 2.87 (2H, t, J = 6.9 Hz), 2.85 (6H, s), 2.79 (2H, t, J = 6.9 Hz), 2.16 (3H, s), 1.89 (2H, quint, J = 6.9 Hz) ).

3- {6- [4- (4-acetylamino) according to the method described in Example 61 using N, N, N′-trimethyl-1,3-propanediamine instead of N, N-dimethylethylenediamine. Phenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminopropyl) -N-methylpropionamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.36 (1H, t, J = 7.8 Hz), 8.01 (1H, d, J = 7.8 Hz), 7.84 (2H, d, J = 9.0 Hz), 7.82 (1H , d, J = 7.8 Hz), 7.72 (2H, d, J = 9.0 Hz), 4.72 (2H, s), 3.40 (2H, t, J = 6.9 Hz), 3.22 (2H, t, J = 6.9 Hz) ), 3.06 (3H, s), 3.06-2.98 (4H, m), 2.82 (6H, s), 2.16 (3H, s).

In the same manner as described in Example 46, using 1- (2-aminoethyl) piperidine instead of N-methylpiperazine, 3- {6- [4- (4-acetylaminophenyl) -6- Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-methylpiperidin-1-ylethyl) propionamide hydrochloride was obtained.
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 8.25-7.61 (3H, m), 7.83 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz ), 7.62 (1H, t, J = 7.8 Hz), 7.35 (1H, d, J = 7.5 Hz), 7.12 (1H, d, J = 7.5 Hz), 4.46 (2H, s) 3.17-3.12 (2H, m), 2.98-2.89 (2H, m), 2.49-2.45 (2H, m), 2.40-2.22 (6H, m), 2.09 (3H, s), 1.30-2.01 (6H, m).

3- {6- [4- (4-acetylaminophenyl) -6-amino in the same manner as described in Example 61 using N, N-diethylethylenediamine instead of N, N-dimethylethylenediamine. -5-Cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-diethylaminoethyl) propionamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.39 (1H, t, J = 8.1 Hz), 8.06 (1H, d, J = 8.1 Hz), 7.83 (2H, d, J = 9.0 Hz), 7.81 (1H , d, J = 8.1 Hz), 7.72 (2H, d, J = 9.0 Hz), 4.73 (2H, s), 3.51 (2H, t, J = 6.3 Hz), 3.30-3.19 (8H, m), 2.82 (2H, t, J = 6.3 Hz), 2.17 (3H, s), 1.29 (6H, t, J = 9.0 Hz).

3- {6- [4- (4-acetylaminophenyl) was prepared in the same manner as described in Example 61 using 1-methyl-4- (methylamino) piperidine instead of N, N-dimethylethylenediamine. ) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N-methyl-N- (1-methylpiperidin-4-yl) propionamide hydrochloride was obtained.
Yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.39 (1H, t, J = 7.8 Hz), 8.03 (1H, d, J = 7.8 Hz), 7.86 (2H, d, J = 9.0 Hz), 7.83 (1H , d, J = 7.8 Hz), 7.73 (2H, d, J = 9.0 Hz), 4.80 (2H, s), 3.64-3.47 (2H, m), 3.24 (2H, t, J = 6.3 Hz), 3.17 -3.12 (1H, m), 2.99 (2H, t, J = 6.3 Hz), 2.98-2.89 (2H, m), 2.91 (3H, s), 2.79 (3H, s), 2.16 (3H, s), 2.10-1.76 (4H, m).

Using 4- (diethylamino) piperidine instead of N, N-dimethylethylenediamine in the same manner as described in Example 61, N- [4- (6-amino-5-cyano-2- {6- [3- (4-Diethylaminopiperidin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
Colorless powder
¹ H-NMR (CD ₃ OD) δ: 8.39 (1H, t, J = 7.2 Hz), 8.03 (1H, d, J = 7.2 Hz), 7.84 (2H, d, J = 8.7 Hz), 7.83 (1H , d, J = 7.2 Hz), 7.72 (2H, d, J = 8.7 Hz), 4.73 (2H, s), 4.58 (1H, br d, J = 12.6 Hz), 4.06 (1H, br d, J = 12.6 Hz), 3.64-3.53 (1H, m), 3.33-2.62 (8H, m), 2.16 (3H, s), 2.16-1.56 (4H, m), 1.35 (6H, t, J = 7.2 Hz).

Using 4-piperidinopiperidine instead of N-methylpiperazine in the same manner as described in Example 46, N- (4- {6-amino-2- [6- (3- [1, 4 ′] bipiperidinyl-1′-yl-3-oxopropyl) pyridin-2-ylmethylsulfanyl] -5-cyanopyrimidin-4-yl} phenyl) acetamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.45 (1H, s), 8.27 (1H, t, J = 7.5 Hz), 7.93 (1H, t, J = 7.5 Hz), 7.81 (2H, d, J = 9.0 Hz), 7.76 (2H, d, J = 9.0 Hz), 7.74 (1H, d, J = 7.5 Hz), 4.76 (2H, s), 4.46 (1H, br d, J = 13.2 Hz), 4.00 (1H, br d, J = 13.2 Hz), 3.35-3.17 (6H, m), 3.05-2.84 (4H, m), 2.56-2.48 (1H, m), 2.15-2.07 (2H, m), 2.10 ( 3H, s), 1.97-1.35 (8H, m).

N- [4- (6-Amino-5-cyano-2- {6- [3] was prepared in the same manner as described in Example 46 using 2-piperidinemethanol instead of N-methylpiperazine. -(2-Hydroxymethylpiperidin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.24 (1H, s), 8.25-7.50 (2H, br s), 7.84 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz) 7.62 (1H, t, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.15 (1H, d, J = 7.8 Hz), 4.47 (2H, s), 3.85-4.70 (5H m), 3.70-3.35 (1H, m), 3.01-2.62 (4H, m), 2.09 (3H, s), 1.80-1.05 (6H, m).

N- [4- (6-Amino-5-cyano-2- {6] was prepared in the same manner as described in Example 46 using 2-piperidin-1-ylmethylmorpholine instead of N-methylpiperazine. -[3-Oxo-3- (2-piperidin-1-ylmethylmorpholin-4-yl) propyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.4 Hz), 7.71 (2H, d, J = 8.4 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.15 (1H, d, J = 7.8 Hz), 4.45 (2H, s), 4.25-3.75 (3H, m), 2.94 (4H, m ), 2.80-2.73 (2H, m), 2.48-2.20 (8H, m), 2.08 (3H, s), 1.42-1.32 (6H, m).

Using 2- (4-ethylpiperazin-1-ylmethyl) morpholine instead of N-methylpiperazine in the same manner as described in Example 46, N- {4- [6-amino-5-cyano- 2- (6- {3- [2- (4-Ethylpiperazin-1-ylmethyl) morpholin-4-yl] -3-oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide The hydrochloride salt was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.4 Hz), 7.71 (2H, d, J = 8.4 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.16 (1H, d, J = 7.8 Hz), 4.46 (2H, s), 4.25-3.75 (3H, m), 2.94-2.73 (4H , m), 2.48-2.20 (13H, m), 2.08 (3H, s), 0.93 (3H, br t).

4- (3- {6- [4- (4-acetylaminophenyl) 4- (3- {6- [4- (4-acetylaminophenyl)] in the same manner as described in Example 61 using 1-tert-butoxycarbonylpiperazine instead of N, N-dimethylethylenediamine. -6-Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} propionyl) piperazine-1-carboxylic acid t-butyl ester was obtained.
White powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 7.83 (2H, d, J = 8.7 Hz), 7.71 (2H, d, J = 8.7 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.16 (1H, d, J = 7.8 Hz), 4.46 (2H, s), 3.41-3.38 (4H, m), 3.30-3.25 (4H m), 2.95 (2H, t, J = 7.5 Hz), 2.73 (2H, t, J = 7.5 Hz), 2.09 (3H, s), 1.39 (9H, s).

N- (4- {6-Amino-5-cyano-2- [6- (3-oxo-3-piperazine) was prepared in the same manner as in Example 60 using the compound obtained in Example 73. -1-ylpropyl) pyridin-2-ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.34 (1H, t, J = 7.8 Hz), 8.00 (1H, d, J = 7.8 Hz), 7.83 (2H, d, J = 8.7 Hz), 7.79 (1H , d, J = 7.8 Hz), 7.71 (2H, d, J = 8.7 Hz), 4.70 (2H, s), 3.77-3.74 (4H, m), 3.29-3.16 (6H, m), 3.04 (2H, t, J = 6.6 Hz), 2.16 (3H, s).

Using 1- (2-diethylaminoethyl) piperazine instead of N, N-dimethylethylenediamine in the same manner as described in Example 61, N- {4- [6-amino-5-cyano-2- (6- {3- [4- (2-Diethylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide hydrochloride was obtained.
Colorless powder
¹ H-NMR (CD ₃ OD) δ: 8.39 (1H, t, J = 7.8 Hz), 8.05 (1H, d, J = 7.8 Hz), 7.86 (1H, d, J = 7.8 Hz), 7.83 (2H , d, J = 9.0 Hz), 7.73 (2H, d, J = 9.0 Hz), 4.73 (2H, s), 3.69-3.07 (20H, m), 2.17 (3H, s), 1.38 (6H, t, J = 7.2 Hz).

Using 1- (2-diisopropylaminoethyl) piperazine instead of N-methylpiperazine in the same manner as described in Example 46, N- {4- [6-amino-5-cyano-2- ( 6- {3- [4- (2-diisopropylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide hydrochloride was obtained.
Colorless powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 7.65-8.20 (2H, br s), 7.84 (2H, d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.62 (1H, t, J = 7.8 Hz), 7.34 (1H, d, J = 7.8 Hz), 7.14 (1H, d, J = 7.8 Hz), 4.47 (2H, s), 3.40-3.29 ( 4H, m), 2.97-2.71 (4H, m), 2.69-2.51 (2H, m), 2.49-2.42 (2H, m), 2.30-2.18 (6H, m) 2.09 (3H, s), 0.92 (12H , d, J = 6.3Hz).

In the same manner as described in Example 61, using 1- [2- (pyrrolidin-1-yl) ethyl] piperazine instead of N, N-dimethylethylenediamine, N- {4- [6-amino- 5-cyano-2- (6- {3-oxo-3- [4- (2-pyrrolidin-1-ylethyl) piperazin-1-yl] propyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] Phenyl} acetamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (DMSO-d ₆ + D ₂ O) δ: 8.09 (1H, t, J = 7.8 Hz), 7.80 (2H, d, J = 9.0 Hz), 7.77 (1H, d, J = 7.8 Hz) ), 7.72 (2H, d, J = 9.0 Hz), 7.57 (1H, d, J = 7.8 Hz), 4.62 (2H, s), 3.58 (2H, t, J = 7.2 Hz), 3.65-3.11 (16H , m), 2.91 (2H, t, J = 7.2 Hz), 2.11 (3H, s), 1.99 (4H, br s).

In the same manner as described in Example 61, using 1- [2- (morpholin-4-yl) ethyl] piperazine instead of N, N-dimethylethylenediamine, N- {4- [6-amino- 5-cyano-2- (6- {3- [4- (2-morpholin-4-ylethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] Phenyl} acetamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.39 (1H, t, J = 8.1 Hz), 8.05 (1H, d, J = 8.1 Hz), 7.85 (1H, d, J = 8.1 Hz), 7.83 (2H , d, J = 8.7 Hz), 7.72 (2H, d, J = 8.7 Hz), 4.73 (2H, s), 4.00 (4H, br s), 3.72 (4H, br s), 3.66-3.27 (14H, m), 3.09 (2H, br s), 2.17 (3H, s).

Using 1- (N-methylpiperidin-4-ylmethyl) piperazine instead of N, N-dimethylethylenediamine in the same manner as described in Example 61, N- {4- [6-amino-5- Cyano-2- (6- {3- [4- (2-diethylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide hydrochloride Got.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.39 (1H, t, J = 8.1 Hz), 8.03 (1H, d, J = 8.1 Hz), 7.84 (3H, br d, J = 9.0 Hz), 7.72 ( 2H, d, J = 9.0 Hz), 4.74 (2H, s), 3.58-2.92 (18H, m), 2.88 (3H, s), 2.28-1.57 (5H, m), 2.17 (3H, s).

Using 1-methylhomopiperazine instead of N, N-dimethylethylenediamine in the same manner as described in Example 61, N- [4- (6-amino-5-cyano-2- {6- [ 3- (4-Methyl- [1,4] diazepan-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.38 (1H, t, J = 7.8 Hz), 8.02 (1H, d, J = 7.8 Hz), 7.84 (2H, d, J = 9.0 Hz), 7.84 (1H , d, J = 7.8 Hz), 7.72 (2H, d, J = 9.0 Hz), 4.72 (2H, s), 4.03-3.05 (12H, m), 2.89 (3H, s), 2.23-2.06 (2H, m), 2.16 (3H, s).

3- {6- [4- (4-acetylaminophenyl) -6 in the same manner as described in Example 61, using 1-amino-4-methylpiperazine instead of N, N-dimethylethylenediamine. -Amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (4-methylpiperazin-1-yl) propionamide hydrochloride was obtained.
Pale yellow powder
¹ H-NMR (CD ₃ OD) δ: 8.40 (1H, t, J = 8.1 Hz), 8.08 (1H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.7 Hz), 7.82 (1H , d, J = 8.1 Hz), 7.72 (2H, d, J = 8.7 Hz), 4.72 (2H, s), 3.48-2.70 (12H, m), 2.85 (3H, s), 2.16 (3H, s) .

Using the compound obtained in Reference Example 17- (2) instead of the compound obtained in Reference Example 11 and according to the same method as in Example 43, N- (4- {6-amino-5-cyano-2- [ 6- (3-Oxopentyl) pyridin-2-ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide was obtained.
Colorless powder
¹ H-NMR (DMSO-d ₆ ) δ: 10.23 (1H, s), 7.83 (2H, d, J = 9.0 Hz), 7.72 (2H, d, J = 9.0 Hz), 7.61 (1H, t, J = 7.5 Hz), 7.33 (1H, d, J = 7.5 Hz), 7.13 (1H, d, J = 7.5 Hz), 4.45 (2H, s), 2.93 (2H, t, J = 6.9 Hz), 2.81 ( 2H, t, J = 6.9 Hz), 2.46 (2H, q, J = 7.2 Hz), 2.09 (3H, s), 0.90 (3H, t, J = 7.2 Hz).
The structures of the compounds obtained in Examples 42 to 82 are shown in Tables 13 to 15 below.

20 mg (25 μM) of the compound obtained in Example 18 (as hydrochloride), various carboxylic acids (30 μM), MP-carbonate (25 μM, manufactured by Argonaut, macroporous polystyrene anion-exchange resin) and 4.5 mg of HOBt-H ₂ O ( 29 μM) was added to methylene chloride-DMF (0.5 mL-0.1 mL) and the resulting suspension was shaken for 1 hour at room temperature. Thereafter, PS-carbodiimide (33 μM, N-Cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene) added to the reaction mixture was shaken at room temperature overnight (about 18 hours). PS-isocyanate (75 μM, manufactured by Argonaut, Polystyrene methylisocyanate) was added to the reaction solution, and the mixture was shaken at room temperature for 3 hours to remove unreacted raw materials. The MP-carbonate was then filtered and washed with 0.2 mL methylene chloride and 0.2 mL DMF. The filtrate and the washing solution were combined, nitrogen gas was blown, methylene chloride was volatilized, the residue was subjected to HPLC under the following conditions, and the product was separated and purified. The purified aqueous solution was lyophilized, the dried product was weighed, and then subjected to LC / MS analysis under the following conditions to confirm its structure.

<HPLC conditions>
Column: CAPCELL PAK C18 (UG 120 S-5, 20mm x 50mm) (Preparative purification)
CAPCELL PAK C18 (UG 120 S-3, 3.0mm × 50mm) (Analysis)
Eluent: 0.05% TFA-MeCN, 0.05% TFA-H ₂ O mixed solution (change solvent ratio as appropriate)
Flow rate: 36 mL / min (preparative purification)
1.8 mL / min (analysis)
<LC / MS analysis conditions>
System: Waters Alliance 2795, Waters ZQ
MS detection: ESI positive.

  By this method, each compound shown in Table 16 to Table 24 below was synthesized. In each table, the theoretical mass number of the obtained compound and the LC / MS observation result ([M + H]) are also shown.

  MP-carbonate (125 μM) was added to a DMF 0.2 mL solution of 20 mg (25 μM) of the compound obtained in Example 18 (as hydrochloride), and the mixture was shaken at room temperature for 3 hours. Thereafter, the reaction mixture is filtered, and the filtrate is added to various sulfonyl chlorides (50 μM) in 0.1 mL of DMF, and then 8.7 μL (50 μM) of diisopropylethylamine is added to the mixture and shaken at room temperature overnight (about 18 hours). did.

  The reaction solution was subjected to HPLC in the same manner under the conditions described in Examples 83-193, and the product was purified by fractionation. The purified aqueous solution was lyophilized, the dried product was weighed, and then subjected to LC / MS analysis in the same manner under the conditions described in Example 83-193 to confirm the structure.

  Table 25 shows the structure, the theoretical mass number, and the LC / MS observation result of the obtained compound.

  A solution obtained by dissolving 16 mg (20 μM) of the compound (as hydrochloride) obtained in Example 18, various alkyl halides (22 μM), and saturated potassium carbonate aqueous solution (100 μM) in 0.2 mL of DMF was allowed to stand overnight at room temperature (about 18 hours). Shake. After diluting the reaction solution by adding 0.2 mL of DMF, the diluted solution was subjected to HPLC in the same manner under the conditions described in Example 83-193, and the product was separated and purified. Further, the purified aqueous solution was freeze-dried, the dried product was weighed, and then subjected to LC / MS analysis in the same manner to confirm the structure.

  Tables 26 to 28 show the structures, theoretical mass numbers, and LC / MS observation results of the obtained compounds.

  Compound of Example 18 (as hydrochloride) To 0.6 mL of a mixture of 20 mg (25 μM) of THF-DMF (3: 1), 28 μL solutions of various aldehydes (28 μM) in DMF and 7 μL (125 μM) of acetic acid were added. MP-cyanoborohydride (63 μM, manufactured by Argonaut, Macroporous triethylammonium methylpolystyrene cyanoborohydride) was added to the reaction mixture, and the mixture was shaken at room temperature for 2 days. MP-cyanoborohydride was removed by filtration, the filtrate was subjected to HPLC in the same manner as described in Example 83-193, and the product was separated and purified. Further, the purified aqueous solution was freeze-dried, the dried product was weighed, and then LC / MS analysis was performed in the same manner to confirm the structure of the product.

  Table 29 to Table 33 show the structure, theoretical mass number, and LC / MS observation results of each compound obtained.

24 mg (50 μM) of the compound obtained in Example 45, various primary or secondary alkyl amines (100 μM) as raw material amines and 8.9 mg (58 μM) of HOBt-H ₂ O were mixed with ethylene chloride-DMF (0.5 mL-0.2 mL). ) Suspended in a mixed solution, and the resulting solution was shaken at room temperature for 10 minutes. When salt-form amines were used as raw materials, MP-carbonate (manufactured by Argonaut) in an equimolar amount with the raw material amines was added to the reaction system. Thereafter, PS-carbodiimide (Argonaut, 67 μM) was added to the reaction mixture, and the mixture was shaken at room temperature overnight (about 18 hours).

  The reaction mixture was filtered and PS-carbodiimide and MP-carbonate (when using the resin) were filtered off and washed with DMF (0.15 mL). The filtrate and washing solution are combined, nitrogen gas is blown to volatilize ethylene chloride, the residue is diluted with 0.15 mL of DMF, and the diluted solution is generated by HPLC under the same conditions as described in Example 83-193. Preparative purification of the product was performed. Further, the purified aqueous solution was freeze-dried, the dried product was weighed, and then LC / MS analysis was performed in the same manner to confirm the structure of the product.

  The structures, theoretical mass numbers, and LC / MS observation results of the obtained compounds are shown in Table 34 to Table 45.

  The following are examples of pharmacological tests conducted on the compounds of the present invention.

(1) c-AMP production action in adenosine A2a receptor-expressing cells This experiment is based on literature (Klotz kN et al., Naunyn-Schmiedeberg's Arch. Pharmacol., (1998) 357, 1-9; Shryock JC et al., The method was described as follows with reference to the method described in Molecular Pharmacology, (1998) 53, 886-893).

  HEK293 cell (PerkinElmer Life Sciences, Code No. RBHA2AC) in which adenosine A2a receptor (Human) was expressed was used as the cell.

  As the medium, Dulbecco's modified Eagles medium (DMEM) containing 10% FBS (Fetal bovine serum) and 1 mM sodium pyruvate was used.

The cells were seeded on a 96 well plate (1 × 10 ⁵ / well) and cultured overnight. After removing the supernatant, add 0.1 mL / well of DMEM (excluding FBS) containing 20 mM HEPES, 0.1 mM IBMX (3-isobutyl-1-methylxanthine) and 2 unit / mL Adenosine deaminase, and incubate at 37 ° C for 30 minutes did. 0.1 mL / well of a medium containing a DMSO solution of a test drug was added to each well so that the test drug concentration in the medium was a predetermined concentration, and further incubated for 30 minutes. After removing the supernatant, a cell lysate was added to stop the reaction. The amount of c-AMP in each well was measured using a c-AMP enzyme immunoassay (EIA) system (Amersham Biosciences, Code No. RPN225).

  The same operation was repeated using CGS-21680 (2-p-carboxyethyl) phenethylamino-5′-N-ethylcarboxamidoadenosine hydrochloride, Sigma, code C141) as a control drug.

  When the concentration of the control drug in the medium at 1 μM is 100 (%), the c-AMP measurement value obtained using each test drug at a predetermined concentration is converted to the value. The concentration of each test drug in the medium in the case of 50 (%) was determined, and this was used as the EC50 value.

The results of the above tests obtained using the following compounds of the present invention produced in the above Examples as test drugs are shown in Table 46 and Table 47 below. In the table, for comparison, the compound described in Example 6 of WO 03/053441 A1 (referred to as Comparative Compound A) having the following structure and the compound described in Example 1 of WO 03/008384 A1 (Comparative) The results of the same test using Compound B) are also shown.
<Comparative Compound A>

<Comparative Compound B>

  From the results shown in Table 46 and Table 47, it is clear that all of the compounds of the present invention have a potent A2a receptor activation action.

(2) Adenosine A1 Agonist Action This experiment is based on literature (Shryock JC et al., Molecular Pharmacology, (1998) 53, 886-893; Ito H. et al., European Journal of Pharmacology, (1999) 365, 309-315 ) Was carried out as follows with reference to the method described in). Specifically, the cerebral cortex of male Wistar rats (Nippon Charles River) was extracted, homogenized with Tris buffer (50 mM Tris-HCl: pH 7.4), and then centrifuged (1000 × g, 10 min). The supernatant was collected and centrifuged (20,000 × g, 20 min). After removing the supernatant, the precipitate was suspended in Tris buffer and centrifuged again (20,000 × g, 20 min). After removing the supernatant, a Tris buffer containing 2 units / mL ADA (adenosine deaminase) was added to the precipitate and suspended therein to prepare a cell membrane preparation for use in subsequent tests. This solution was stored at −80 ° C. until use.

In addition to the Tris-buffer containing 5 mM MgCl ₂ , 1 mM EDTA, 1 mM dithiothreitol, 100 mM NaCl, 0.01 mM GDP (guanosine diphosphate), 5 mg / mL BSA and 2 units / mL ADA And incubated at 25 ° C. for 30 minutes. Furthermore, [ ³⁵ S] GTPγS (Guanosine 5 ′-[γ-thio] triphosphate) (final concentration 0.4 nM) and a test compound having a predetermined concentration (concentration converted from the final concentration of the test compound) were added, and the mixture was added at 25 ° C. for 45 minutes. Incubated. The reaction mixture was filtered through a glass fiber filter (unifilter-96 GF / B, Perkin Elmer Life Sciences) to stop the reaction. The filter was washed five times with ice-cooled Tris-buffer containing 5 mM MgCl ₂ . The radioactivity of the filter was measured with Top count NXT (Perkin Elmer Life Sciences). Nonspecific binding was expressed as [ ³⁵ S] GTPγS binding activity in the presence of 0.01 mM GTPγS.

The relative activity (%) of each test compound was defined with the result of the above test ([ ³⁵ S] GTPγS binding activity) obtained using 1 μM CPA (N ⁶ -Cyclopentyladenosine, Sigma, code C-8031) as a control drug being 100%. , A1 agonistic action) was calculated.

  Table 48 below shows the test results when 1 μM, 100 nM, and 10 nM of the compound of the present invention (including salts thereof) obtained in the above Examples were used as test compounds, respectively. Table 48 also shows the results when the comparative compounds A and B described in the pharmacological test example (1) are used as the comparative compounds.

  From the results shown in Table 48, the following is clear. That is, the A1 receptor activating action (A1 agonistic action) of the compound of the present invention is considerably weaker than that of the comparative compound, which indicates that the compound of the present invention can selectively act on the adenosine A2a receptor. .

  As a result of conducting the same test on the compounds of the present invention obtained in the respective examples other than the compounds of the present invention described in Table 48 above, almost all of the compounds were A1 agonists similar to those of the compounds of the present invention shown in Table 48. It was confirmed to show an action.

(3) Rabbit intraocular pressure measurement test A test compound was prepared in a solution or suspension of a predetermined concentration using a 10 mM phosphate buffer (pH 7.5) (hereinafter referred to as eye drop base) and used for the test. That is, in the case of a test compound that does not completely dissolve when adjusted to a predetermined concentration, it was used as a suspension at that concentration.

  NewZealand female white rabbits (Kitayama Labes) weighing 2.0-4.0 kg were used for the test.

Intraocular pressure measurement was performed without anesthesia using a Pneumatonometer (Model 30 Classic, Mentor). Further, prior to the measurement of intraocular pressure, surface anesthesia was performed with 0.4% oxybuprocaine hydrochloride (“Benoxeal ^™ ” 0.4% ophthalmic solution, Santen Pharmaceutical).

  An animal with stable intraocular pressure was selected, and 50 μL of the test compound was instilled into one eye as 4 animals per group, and an eye drop base was administered with the opposite eye as the control eye. Intraocular pressure was measured before instillation and 0.5, 1, 2, 3, 4 and 6 hours after instillation, respectively. The effect on intraocular pressure was expressed as the amount of change from the pre-instillation value (ΔIOP, mmHg, mean ± standard error). As test compounds, the results obtained using Comparative Compounds A and B described in the Pharmacological Test Example (1) (both used as a 1% suspension) are shown in Table 49 and Table 50 below for each test compound. Shown in

  Animals were pretreated in the same manner as described above, and animals with stable intraocular pressure were selected. Two groups were used for each test compound as 5-8 animals in each group. The test compound was administered to one eye of a rabbit in the administration group, and the intraocular pressure was measured. An eye drop base was administered to one eye of a rabbit in a control group, and the intraocular pressure was measured. As described above, intraocular pressure measurement was performed before instillation, 0.5, 1, 2, 3, 4 and 6 hours after instillation. )

  The results obtained using each of the control compound CGS-21680 and the compound of the present invention (compounds obtained in Examples) as test compounds are shown in Table 51 to Table 67 below for each test compound.

  As a result of conducting the same test on the compounds of the present invention obtained in Examples 1 to 84 other than the compounds of the present invention described in Table 51 to Table 67, all the compounds were almost the same as the results shown in Table 51 to Table 67. It was confirmed to give similar results.

  The following is clear from the results shown in Table 49 to Table 67.

  That is, as shown in Table 49 and Table 50, Comparative Compounds A and B did not show a significant intraocular pressure-lowering effect even at a relatively high concentration of 1% suspension.

  As shown in Tables 52 to 67, all of the tested compounds of the present invention exhibited an intraocular pressure-lowering effect. In particular, the compounds of the present invention shown in Tables 54 to 67 show equivalent intraocular pressure-lowering effects at a lower concentration than the compounds compared to CGS-21680 (see Table 51), which has already been reported to have intraocular pressure-lowering effects. It was. Further, the compounds of the present invention shown in Table 55 to Table 67 are soluble at high concentrations (0.3% to 1%) higher than the tested concentrations (0.01% to 0.03%) without solubilizing agents. As useful.

Claims (5)

General formula (1):

[Where
R ¹ represents a hydrogen atom, a lower alkylcarbonyl group, a lower alkenylcarbonyl group, a phenylcarbonyl group or a lower alkoxycarbonyl group.
R ² represents a lower alkylene group.
R ³ represents (1) a hydrogen atom, (2) a lower alkyl group, or any of the following groups (3) to (12).

In the groups (3) to (12), R ⁴ is a lower alkylene group, R ⁵ is a hydrogen atom or a lower alkyl group, R ⁶ is a lower alkenylene group, R ⁷ is a lower alkynylene group, and R ⁸ is a lower alkyl group. Z ^{1 to} Z ³ each represent any group selected from the group consisting of the following (a1)-(a38), (b1)-(b8) and (c1)-(c22).
Z ¹ : (a1) lower alkyl group, (a2) aryl lower alkyl group, (a3) aminoaryl lower alkyl group, (a4) aryl lower alkenyl group, (a5) heteroaryl lower alkyl group, (a6) heteroaryl lower Alkenyl group, (a7) heteroarylaryl lower alkyl group, (a8) hydroxy lower alkyl group, (a9) aryloxy lower alkyl group, (a10) amino lower alkyl group, (a11) aminocarbonyl lower alkyl group, (a12) Lower alkylcarbonyl group, (a13) lower alkoxy lower alkylcarbonyl group, (a14) amino lower alkylcarbonyl group, (a15) arylcarbonyl group, (a16) aryl lower alkylcarbonyl group, (a17) aryl lower alkenylcarbonyl group, a18) aryloxy lower alkylcarbonyl group, (a19) heteroarylcarbonyl group, (a20) heteroaryl lower alkylcarbonyl group Group, (a21) heteroaryl lower alkenylcarbonyl group, (a22) heteroaryloxy lower alkylcarbonyl group, (a23) heteroarylsulfanyl lower alkylcarbonyl group, (a24) heteroarylarylcarbonyl group, (a25) arylsulfanyl lower alkyl Carbonyl group, (a26) arylcarbonyl lower alkylcarbonyl group, (a27) arylamino lower alkylcarbonyl group, (a28) lower alkoxycarbonyl group, (a29) lower alkylsulfonyl group, (a30) arylsulfonyl group, (a31) hetero An arylsulfonyl group, (a32) a hydrogen atom, (a33) a lower alkyl group having a saturated heterocyclic ring, (a34) a carbonyl lower alkyl group having a saturated heterocyclic ring, (a35) an aryl lower alkyl group having a saturated heterocyclic ring, (a36) ) A carbonyl group having a saturated heterocyclic ring; (a37) a lower alkyl group having a saturated heterocyclic ring. A bonyl group, (a38) an arylcarbonyl group having a saturated heterocyclic ring;
The amino group constituting a part of each group described in the above (a3), (a10), (a11) and (a14) is selected from the group consisting of a lower alkyl group, a carbonyl group and a lower alkylcarbonyl group. One or two of the substituents may be substituted, and one of each group described in the above (a2), (a15), (a16), (a17), (a18), (a30) and (a35) The aryl group constituting the part is halogen, hydroxyl group, lower alkyl group, lower alkoxy group, halogeno lower alkoxy group, aryl group, aryloxy group, methylenedioxy group, dihalogenomethylenedioxy group, carboxyl group, lower alkoxycarbonyl Group, a lower alkylcarbonyloxy group, a nitro group, a lower alkylamino group, a lower alkylcarbonylamino group, and an aminosulfonyl group may be substituted with 1 to 3 substituents selected from the group (a 5), heteroaryl group constituting a part of each group described in (a19) to (a24) and (a31) is halogen, hydroxyl group, lower alkyl group, hydroxy lower alkyl group, halogeno lower alkyl group, aryl group , A halogenoaryl group, a lower alkylsulfanyl group, an aminocarbonyl group and a carboxyl group may be substituted with 1 to 3 substituents. Furthermore, the saturated heterocyclic ring constituting a part of each group described in the above (a33) to (a38) is a 5- to 7-membered nitrogen-containing saturated heterocyclic group or 1 to 2 benzene rings in the group. The condensed group may have one lower alkyl group or lower alkylcarbonyl group on the nitrogen atom constituting the ring, and 1 or 2 carbon atoms constituting the ring It may have an oxo group.
Z ² : (b1) a hydrogen atom, (b2) a lower alkoxycarbonyl group, (b3) an amino lower alkylcarbonyl group, (b4) a lower alkenylcarbonyl group, (b5) a lower alkylcarbonyl group having a saturated heterocyclic ring, (b6) A piperidino lower alkylcarbonyl group having a saturated heterocyclic ring, (b7) a carbonyl group having a saturated heterocyclic ring, and (b8) a lower alkylsulfonyl group.
The amino group constituting a part of each group described in the above (b3) may be substituted with 1 or 2 lower alkyl groups. Further, the saturated heterocyclic ring constituting a part of each group described in the above (b5) to (b7) is a 5- to 7-membered nitrogen-containing saturated heterocyclic group and is on the nitrogen atom constituting the ring. It may have one lower alkyl group.
Z ³ : (c1) hydroxyl group, (c2) lower alkoxy group, (c3) amino group, (c4) amino lower alkylamino group, (c5) piperazino group, (c6) amino lower alkyl piperazino group, (c7) Aminocarbonyl lower alkyl piperazino group, (c8) 1,4-diazepan-1-yl group, (c9) amino lower alkyl-1,4-diazepan-1-yl group, (c10) piperidino group, (c11) An aminopiperidino group, (c12) an amino lower alkylaminopiperidino group, (c13) an amino lower alkylpiperidino group, (c14) a pyrrolidino group, (c15) an amino group having a saturated heterocyclic ring, and (c16) a saturated heterocyclic ring. (C17) a piperazino group having a saturated heterocyclic ring, (c18) a lower alkyl piperazino group having a saturated heterocyclic ring, (c19) a carbonyl lower alkyl piperazino group having a saturated heterocyclic ring, (c20 ) Lower alkyl-1,4-diazepan-1-yl group having a saturated heterocyclic ring, (c21) saturated heterocyclic ring Lower alkyl morpholino group having a piperidino group, and (c22) a saturated heterocyclic ring having.
Incidentally, the amino group of the above (c3), and each of (c4), (c6), (c7), (c9), (c11), (c12), (c13), (c15) and (c16) The amino group constituting a part of the group is a lower alkyl group, a hydroxy lower alkyl group, an aryl group, a heteroaryl group, an aryl lower alkyl group, an alkyloxyaryl lower alkyl group, a heteroaryl lower alkyl group and a lower alkoxycarbonyl group. The amino group constituting a part of the group described in (c11) above may be substituted with one aryl lower alkylcarbonyl group, which may be substituted with one or two substituents selected from the group consisting of It may be. In addition, the piperazino group in (c5) and the 1,4-diazepan-1-yl group in (c8) have a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group, a lower alkyl aryl at the 4-position. Group, hydroxyaryl group, cyanoaryl group, halogenoaryl group, aryl lower alkyl group, lower alkoxyaryl lower alkyl group, halogenoaryloxy lower alkyl group, heteroaryl group, lower alkyl heteroaryl group, halogeno lower alkyl heteroaryl group, It may have any one of substituents selected from the group consisting of a cyanoheteroaryl group, a heteroaryl lower alkyl group, a lower alkoxycarbonyl group and a lower alkylcarbonyl group. Furthermore, the saturated heterocyclic ring constituting a part of each group described in the above (c15) to (c22) is a 5- to 7-membered nitrogen-containing saturated heterocyclic group, and the group includes 1 to 2 saturated heterocyclic rings. The benzene ring may be condensed, and the group may be formed from a lower alkyl group, an aryl group, a cyanoaryl group, a lower alkylcarbonyl group, a halogeno lower alkylaryl group and an aryl lower alkyl group on a nitrogen atom constituting the benzene ring. Any one of substituents selected from the group consisting of: Furthermore, the piperazino group of (c5), the piperidino group of (c10) and the saturated heterocyclic ring constituting a part of each group described in (c15) to (c22) are on the carbon atoms constituting these rings. It may have any one of substituents selected from the group consisting of a hydroxyl group, an oxo group, a lower alkyl group, a hydroxy lower alkyl group, an aryl group, an aryl lower alkyl group, an aminocarbonyl group and a lower alkylamino group. . ]
A 4-amino-5-cyanopyrimidine derivative represented by the formula or a pharmaceutically acceptable salt thereof. R ³ is

[Wherein R ⁴ has the same definition as R ⁴ in claim 1. Z ³ is (c3) amino group, (c4) amino lower alkylamino group, (c5) piperazino group, (c6) amino lower alkylpiperazino group, (c8) 1,4-diazepan-1-yl group, (c10) piperidino group, (c11) aminopiperidino group, (c18) lower alkyl piperazino group having a saturated heterocyclic ring, (c21) piperidino group having a saturated heterocyclic ring, or (c22) lower alkyl morpholino group having a saturated heterocyclic ring Indicates.
The amino group constituting the above (c3) amino group and a part of each group described in (c4), (c6) and (c11) are a lower alkyl group, a hydroxy lower alkyl group, a phenyl group, -Methylpiperidin-4-yl group, 4-methylpiperazino group, 2- (1-piperidyl) ethyl group and lower alkoxycarbonyl group may be substituted with 1 or 2 substituents, The amino group constituting a part of the group described in (c11) may be substituted with one phenyl lower alkylcarbonyl group. In addition, the piperazino group of (c5) and the 1,4-diazepan-1-yl group of (c8) have a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, a phenyl group, a lower alkyl phenyl group at the 4-position. Group, hydroxyphenyl group, cyanophenyl group, halogenophenyl group, phenyl lower alkyl group, lower alkoxyphenyl lower alkyl group, halogenophenyloxy lower alkyl group, pyridyl group, lower alkylpyridyl group, halogeno lower alkylpyridyl group, cyanopyridyl group , Any one of substituents selected from the group consisting of a pyridyl lower alkyl group, a lower alkoxycarbonyl group, and a lower alkylcarbonyl group. Further, the saturated heterocyclic ring constituting a part of each group described in the above (c18) and (c22) is pyrrolidyl, pyrrolidino, piperidyl, piperidino, piperazyl, piperazino, 1,4-diazepan-1-yl, tetrahydrofuryl. 1,3-dioxolanyl, tetrahydrothienyl, morpholyl, morpholino and tetrahydroimidazolyl, and means a monovalent saturated heterocyclic group selected from the group consisting of a lower alkyl group on the nitrogen atom constituting the group. Any one of substituents selected from the group consisting of phenyl group, cyanophenyl group, lower alkylcarbonyl group, halogeno lower alkylphenyl group, and phenyl lower alkyl group. Further, each of the piperazino group in (c5), the piperidino group in (c10), the lower alkyl piperazino group having a saturated heterocyclic ring in (c18) or the lower alkylmorpholino group having a saturated heterocyclic ring in (c22). The saturated heterocyclic ring constituting a part of the group is a hydroxyl group, an oxo group, a lower alkyl group, a hydroxy lower alkyl group, a phenyl group, a phenyl lower alkyl group, an aminocarbonyl group and a lower alkyl on the carbon atoms constituting these rings. It may have any one substituent selected from the group consisting of amino groups. ]
The 4-amino-5-cyanopyrimidine derivative according to claim 1 or a pharmaceutically acceptable salt thereof. R ³ is

[Wherein R ⁴ has the same definition as R ⁴ in claim 1.
Z ³ is
(c3) substituted with one or two substituents selected from the group consisting of a lower alkyl group, 1-methylpiperidin-4-yl group, 4-methylpiperazino group and 2- (1-piperidyl) ethyl group Good amino group,
(c4) an amino lower alkylamino group optionally substituted with one or two substituents selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group on the amino group;
(c5) a piperazino group optionally substituted with one substituent selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group,
(c6) an amino lower alkyl piperazino group optionally substituted with one or two lower alkyl groups on the amino group,
(c8) 1,4-diazepan-1-yl group optionally substituted with one lower alkyl group,
(c10 ) 2 -hydroxymethylpiperidino group,
(c11) an aminopiperidino group optionally substituted with one or two lower alkyl groups on the amino group;
(c18) A lower alkyl piperazino group having a saturated heterocyclic group selected from the group consisting of pyrrolidyl, pyrrolidino, piperidyl, piperidino, morpholyl and morpholino groups (lower alkyl group 1 on the nitrogen atom constituting the heterocyclic group) pieces may have),
(c21) 4- (1-piperidyl) piperidino group or
(c22) a lower alkylmorpholino group having a saturated heterocyclic ring selected from the group consisting of piperidyl, piperidino, piperazyl and piperazino groups (which may have one lower alkyl group on the nitrogen atom constituting the heterocyclic group) )
Indicates. ]
The 4-amino-5-cyanopyrimidine derivative according to claim 2 or a pharmaceutically acceptable salt thereof. R ¹ is a hydrogen atom or a lower alkylcarbonyl group, R ² is a methylene group, R ³ is

[Where Z ³ is
(c3) One or two substituents selected from the group consisting of a lower alkyl group, 1-methylpiperidin-4-yl group, 4-methylpiperazino group and 2- (1-piperidyl) ethyl group may be substituted. An amino group,
(c4) an amino lower alkylamino group optionally having 1 or 2 substituents selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group on the amino group;
(c5) a piperazino group optionally substituted by one substituent selected from the group consisting of a lower alkyl group and a lower alkoxycarbonyl group;
(c6) an amino lower alkyl piperazino group optionally substituted with one or two lower alkyl groups on the amino group,
(c8) 1,4-diazepan-1-yl group optionally substituted with one lower alkyl group,
(c10 ) 2 -hydroxymethylpiperidino group,
(c11) an aminopiperidino group in which one or two lower alkyl groups may be substituted on the amino group,
(c18) a pyrrolidino-lower alkyl piperazino group, (which may have one lower alkyl group on the nitrogen atom constituting the piperidyl group) piperidyl-lower alkyl piperazino groups or morpholino-lower alkylpiperazino Group,
(c21) 4- (1-piperidyl) piperidino group or
(c22) A piperidino lower alkylmorpholino group or piperazino lower alkylmorpholino group (which may have one lower alkyl group on the nitrogen atom constituting the piperazino group). ]
The 4-amino-5-cyanopyrimidine derivative according to claim 3 or a pharmaceutically acceptable salt thereof. The 4-amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is selected from the following 1) to 15).
1) N- [4- (6-Amino-5-cyano-2- [6- [3- (4-methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl] pyrimidine- 4-yl) phenyl] acetamide,
2) 3- [6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl] -N- (2-dimethylaminoethyl) propion Amide,
3) 3- [6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl] -N- (2-dimethylaminoethyl)- N-methylpropionamide,
4) 3- [6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl] -N- (2-dimethylaminopropyl)- N-methylpropionamide,
5) 3- [6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl] -N- [2- (piperidine-1- Yl) ethyl] propionamide,
6) 3- [6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl] -N- (2-diethylaminoethyl) propionamide ,
7) 3- [6- [4- (4-Acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl] -N-methyl-N- (1-methyl Piperidin-4-yl) propionamide,
8) N- (4- [6-Amino-2- [6- (3- [1,4 '] bipiperidinyl-1'-yl-3-oxopropyl) pyridin-2-ylmethylsulfanyl] -5-cyano Pyrimidin-4-yl] phenyl) acetamide,
9) N- [4- (6-Amino-5-cyano-2- [6- [3-oxo-3- (2-piperidin-1-ylmethylmorpholin-4-yl) propyl] pyridin-2-yl Methylsulfanyl] pyrimidin-4-yl) phenyl] acetamide,
10) N- [4- [6-Amino-5-cyano-2- (6- [3- [2- (4-ethylpiperazin-1-ylmethyl) morpholin-4-yl] -3-oxopropyl] pyridine -2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl] acetamide,
11) N- [4- [6-Amino-5-cyano-2- (6- [3- [4- (2-diisopropylaminoethyl) piperazin-1-yl] -3-oxopropyl] pyridine-2- Ylmethylsulfanyl) pyrimidin-4-yl] phenyl] acetamide,
12) N- [4- [6-Amino-5-cyano-2- (6- [3-oxo-3- [4- (2-pyrrolidin-1-ylethyl) piperazin-1-yl] propyl] pyridine- 2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl] acetamide,
13) N- [4- [6-Amino-5-cyano-2- (6- [3- [4- (2-morpholin-4-ylethyl) piperazin-1-yl] -3-oxopropyl] pyridine- 2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl] acetamide,
14) N- [4- [6-Amino-5-cyano-2- (6- [3- [4- (2-diethylaminoethyl) piperazin-1-yl] -3-oxopropyl] pyridin-2-yl Methylsulfanyl) pyrimidin-4-yl] phenyl] acetamide,
15) N- [4- (6-Amino-5-cyano-2- [6- [3- (4-methyl- [1,4] diazepan-1-yl) -3-oxopropyl] pyridine-2- Ylmethylsulfanyl] pyrimidin-4-yl) phenyl] acetamide.