4-amino-5-cyanopyrimidine derivatives

European).

DESCRIPTION

The present invention relates to a useful drug as an adenosine A2a receptor agonist containing a 4-amino-5-cyanopyrimidine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical formulation containing these compounds.

Background of the invention

Adenosine is a substance that can have a variety of physiological effects when it binds to a receptor on the cell surface. The cell surface adenosine receptor belongs to the family of receptors associated with G proteins and is classified into A1, A2a, A2b and A3. Among them, adenosine A1 and adenosine A3 receptors are bound to the Gi protein and their activation causes a decrease in the level of intracellular c-AMP. In addition, adenosine A2a and adenosine A2b receptors are bound to the Gs protein and their activation causes an increase in intracellular c-AMP. These four types of adenosine receptor subtypes have been cloned.

Various studies on agonists and antagonists that may act at any of the above types of adenosine receptor have already been described. It has been disclosed that these agonists and antagonists could be used as medicaments for the treatment of cardiovascular disorder, ischemia-reperfusion injury, inflammation, Parkinson's disease, schizophrenia, etc. In particular, many adenosine derivatives have been reported as active agonists for the A2a adenosine receptor (see publications 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 5 877 180, WO 00/044763 Al, WO 93/22328 Al, JP-B-1-33477, JP-B- 2774169, US

4968697, JP-A-63-201196, JP-A-2003-055395 and JP-A-2002-173427).

In addition, compounds that are structurally different from the above adenosine derivatives and have no adenine structure are also shown as active agonists for the A1 or A2 adenosine receptor. Examples of compounds include dicyanopyridine derivatives (see 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 and WO 03/053441 A1). However, cyanopyrimidine derivatives having an effect that can activate the A2a adenosine receptor are not known.

On the other hand, glaucoma is an incurable eye disease that most mammal species, including primates, can suffer from. The symptoms observed are blurred vision and eye pain or loss of vision, and the optic nerve disorder may affect the field of vision, in some cases leading to blindness. Glaucoma can be classified into two types: ocular hypertension glaucoma, which is characterized by an increase in intraocular pressure (an intraocular pressure pathway) and glaucoma at normal pressure without any intraocular pressure pathway. The pacing of intraocular pressure in glaucoma can be caused by a loss of balance between the flow rate of aqueous humor that is secreted from the epithelium into the posterior chamber and the outflow rate of the aqueous humor that is expelled from the anterior chamber mainly through the Schlemm's channel.

This loss of balance is thought to be caused by increased resistance to the aqueous humor of the eye, mainly due to blockage of the aqueous humor. Glaucoma is a significant disease which, with the progress of aging, from year to year the number of patients increases in every developed country, and therefore social pressure regarding the development of medicine should increase.

Currently, in the treatment of glaucoma, the control of intraocular pressure, which is the most important problem, and the drugs used to treat it, include δ blockers such as carteolol and timolol, prostagaglide derivatives such as latanoprost and unoprostone isopropyl, carbonic anhydrase inhibitors such as dorzolamide. These medications can modulate the formation or drainage of aqueous humor to reduce intraocular pressure.

Adenosine A2a receptor agonists have not only been reported to exhibit strong antihypertensive activity and are useful as the above-mentioned drugs such as antihypertensive drug, drug for the treatment / prevention of ischemic heart or brain disease, and antihardening drug, but also have ocular hypotensive effect ( see J. Pharmcol. Exp. Ther. 320-326,273 (1995) and Eur. J. Pharmacol. 307-316,486 (2004)).

In addition, with respect to adenosine derivatives having an intraocular pressure lowering effect, their research and development are partially progressing (see JP-A-2003-055395 and JP-A2002-173427).

However, there is concern that these adenosine derivatives could be accompanied by some side effects on the central nervous system and cardiovascular system when these compounds are used as medicaments for the treatment of glaucoma.

As mentioned above, adenosine derivatives having an adenine structure are expected to have activity as adenosine A2a receptor agonists, especially as a drug for the treatment of glaucoma, etc., because of their intraocular pressure lowering effect, but the intraocular pressure lowering effect is not sufficient, moreover, these the compounds have a dangerous disadvantage in the form of side effects on the central nervous and cardiovascular systems, for example a strong antihypertensive effect generated by a strong agonist activity at the A2a adenosine receptor resulting from their adenine structure. Therefore, a related field is required to develop a compound that may exhibit a desirable reduction in intraocular pressure as an adenosine A2a receptor agonist, especially a drug for the treatment of glaucoma and can be used more safely instead of the above compounds. Disclosure of the Invention

Problem to be Solved by the Invention The object of the present invention is to provide a compound exhibiting a safe and potent agonist activity at the A2a adenosine receptor and to provide an adenosine A2a receptor agonist as an intraocular pressure reducing agent, a drug for the treatment of glaucoma comprising this compound as an active ingredient.

Means for Solving the Problem. The present inventors have conducted extensive research to achieve the above goal and have been successful in producing certain types of 4-amino-5-cyanopyrimidine derivatives, and have also found that the compounds showed strong agonist activity at the A2a adenosine receptor. The present invention has been supplemented with additional research based on these findings.

The present invention provides compounds as set forth in items 1-13 below and a pharmaceutical composition thereof.

1. The 4-amino-5-cyanopyrimidine derivative of formula (1):

NHR¹

NC

H 2 N

N

SR2 _R3 (1) or a pharmaceutically acceptable salt thereof, in which

R¹ is hydrogen, lower alkylcarbonyl, lower alkenylcarbonyl, phenylcarbonyl or lower alkoxycarbonyl;

R² is lower alkylene;

R³ means any of (1) a hydrogen atom, (2) lower alkyl or any of the following groups (3) - (12):

<td>-R⁴—N \&gt;</td><td>L ^ o</td>

<td>Group (3)</td><td>Group (4)</td>

<td>II</td><td>R4 N.</td>

<td>C-OR⁵</td><td> \ /</td>

<td>Group (5)</td><td>Group (6)</td>

<td></td><td>ABOUT O-, T</td><td>CC1</td><td>R4 NZ2 AND</td>

<td>10 Group (7)</td><td>V</td><td>J</td><td>R5 Group (8)</td>

<td>Group (9)</td><td>ABOUT -rU-</td><td>Z3</td><td>ABOUT -R⁶C-Z³Group (10)</td>

<td></td><td></td><td></td><td></td>

<td></td><td>ABOUT -r7_C__FROM3</td><td></td><td>ABOUT -R⁴-C-R⁸</td>

<td>Group (11)</td><td></td><td>Group (12)</td><td></td>

in which

R⁴ is lower alkylene, R⁵ is hydrogen or lower-alkyl, R⁶ is lower alkenylene, R⁷ is lower alkynylene, and R⁸ is lower alkyl;

FROM¹, FROM², and Z³ are selected from (a1) - (a38), (b1) - (b8), and (c1) - (c22) as defined below:

FROM¹: (a1) lower alkyl, (a2) aryl-lower alkyl, (a3) ​​aminoaryl-lower alkyl, (a4) aryl-lower alkenyl, (a5) heteroaryl-lower alkyl, (a6) heteroaryl-lower alkenyl, (a7) heteroarylaryl -lower alkyl, (a8) hydroxy-lower alkyl, (a9) aryloxy-lower alkyl, (a10) amino-lower alkyl, (a11) aminocarbonyl-lower alkyl, (a12) lower alkyl-carbonyl, (a13) lower alkoxy- lower alkylcarbonyl, (a14) amino-lower alkylcarbonyl, (a15) arylcarbonyl, (a16) aryl lower alkylcarbonyl, (a17) aryl-lower alkenylcarbonyl, (a18) aryloxy-lower alkylcarbonyl, (a19) heteroarylcarbonyl, (a20) heteroaryl-lower alkylcarbonyl, (a21) heteroaryl-lower alkenylcarbonyl, (a22) heteroaryloxy-lower alkylcarbonyl, (a23) heteroalkylsyl lower alkylcarbonyl, (a24) heteroaryl arylcarbonyl, (a25) aryl sulfanyl lower alkylcarbonyl, (a26) arylcarbonyl-lower alkylcarbonyl, (a27) arylamino-lower alkylcarbonyl, (a28) lower alkoxycarbonyl, (a29) lower alkylsulfonyl, (a30) arylsulfonyl, (a31) heteroarylsulfonyl, (a32) hydrogen, (a33) lower alkyl substituted with saturated heterocycle, (a34) carbonyl-lower alkyl substituted with saturated heterocycle, (a35) aryl-lower alkyl substituted with saturated heterocycle, ( a36) carbonyl substituted saturated heterocycle, (a37) lower alkylcarbonyl substituted saturated heterocycle, or (a38) arylcarbonyl substituted saturated heterocycle;

the amino moiety included as part of the groups in the above (a3), (a10), (a11) and (a14) may be optionally substituted with 1 or 2 substituents selected from the group consisting of lower alkyl, carbonyl, and lower alkyl carbonyl;

the aryl moiety included as part of the groups in the above (a2), (a15), (a16), (a17), (a18), (a30) and (a35) may be optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, halo-lower alkoxy, aryl, aryloxy, methylenedioxy, dihalomethylenedioxy, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, nitro, lower alkylamino, lower alkylcarbonylamino and aminosulfonyl;

the heteroaryl moiety included as part of the groups in the above (a5), (a19) - (a24) and (a31) may be optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, lower alkyl, hydroxy lower alkyl, halogen lower alkyl , aryl, haloaryl, lower alkylsulfanyl, aminocarbonyl and carboxyl; and the saturated heterocycle moiety incorporated as part of the groups in the above (a33) - (a38) can be a 5- to 7-membered saturated nitrogen-containing heterocyclic group or the above heterocyclic group fused to 1 to 2 benzene rings, optionally substituted with lower alkyl or lower alkylcarbonyl on a nitrogen atom in the ring system, or optionally substituted with 1 or 2 oxo groups on carbon atoms in the ring system;

FROM²: (b1) hydrogen atom, (b2) lower alkoxycarbonyl, (b3) amino-lower alkylcarbonyl, (b4) lower alkenyl carbonyl, (b5) lower alkylcarbonyl substituted with saturated heterocycle, (b6) piperidine-lower alkylcarbonyl substituted with saturated heterocycle, ( b7) carbonyl substituted saturated heterocycle, or (b8) lower alkylsulfonyl;

the amino group included as part of the groups in the above (b3) may be optionally substituted with 1 or 2 lower alkyl groups; and the saturated heterocycle moiety incorporated as part of the groups in the above (b5) - (b7) may be a 5- to 7-membered saturated nitrogen containing heterocyclic group optionally substituted with lower alkyl on a ring nitrogen atom;

FROM³: (c1) hydroxyl, (c2) lower alkoxy, (c3) amino group, (c4) amino-lower alkylamino group, (c5) piperazine group, (c6) amino-lower alkylpiperazine group, (c7) aminocarbonyl-lower alkylpiperazine group, (c8) 1,4-diazepan-1-yl group, (c9) amino-lower alkyl group 1,4-diazepan-1-yl group, (c10) piperidine group, (c11) aminopiperidine group, (c12) amino-lower group alkylaminopiperidine, (c13) amino-lower alkylpiperidine group, (c14) pyrrolidine group, (c15) saturated heterocycle substituted amino group, (c16) saturated heterocycle substituted lower alkylamino group, (c17) saturated heterocycle substituted piperazine group, (c18) saturated saturated heterocycle substituted lower alkylpiperazine group, (c19) saturated saturated lower alkyl alkyl piperazine group heterocycle, (c20) lower alkyl-1,4-diazepan-1-yl substituted with saturated heterocycle, (c21) piperidine substituted with saturated heterocycle, or (c22) lower alkyl morpholine group substituted with a saturated heterocycle;

the amino group in the above (c3) and the amino moiety included as part of the groups in the above (c4), (c6), (c7), (c9), (c11), (c12), (c13), (c15) and (c16 ) may be optionally substituted with 1 or 2 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, aryl, heteroaryl, aryl-lower alkyl, alkoxyaryl-lower alkyl, heteroaryl lower alkyl and lower alkoxycarbonyl;

the amino moiety incorporated as part of the groups in the above (c11) may be optionally substituted with aryl-lower alkylcarbonyl;

the piperazine group in the above (c5) and the 1,4-diazepan1-yl group in the above (c8) can be substituted with any of the substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, aryl, lower alkylaryl , hydroxyaryl, cyanoaryl, halo-aryl, aryl-lower alkyl, lower alkoxyaryl-lower alkyl, haloaryloxy-lower alkyl, heteroaryl, lower alkyl-heteroaryl, halo-lower alkylheteroaryl, cyano-heteroaryl, heteroaryl lower alkyl, lower alkoxycarbonyl and lower alkylcarbonyl at the 4-position of the ring system; furthermore, the saturated heterocycle moiety incorporated as part of the groups in the above (c15) - (c22) may be a 5- to 7-membered saturated nitrogen-containing heterocyclic group or the above heterocyclic group fused with 1 to 2 benzene rings, optionally having any of the substituents selected from lower alkyl, aryl, cyanoaryl, lower alkylcarbonyl, halo-lower alkylaryl and aryl lower alkyl on a ring nitrogen atom; and further, the piperazine group in the above (c5), the piperidine group in the above (c10) and the saturated heterocycle group included as part of the groups in the above (c15) - (c22) can be substituted with any of the substituents selected from the group consisting of hydroxyl, oxo , lower alkyl, hydroxy-lower alkyl, aryl, aryl-lower alkyl, aminocarbonyl and lower alkylamino on the ring carbon atom, wherein the term "lower alkyl" as used herein means a straight or branched chain alkyl group having 1 to 6 carbon atoms;

the terms "lower alkoxy" and "lower alkylene" also mean respectively a straight or branched chain alkoxy group and an alkylene group containing 1 to 6 carbon atoms;

the terms "lower alkenyl", "lower alkenylene", and "lower alkynylene" mean respectively an alkenyl group, an alkenylene group and a straight or branched chain alkynylene group having 2 to 6 carbon atoms.

2. The 4-amino-5-cyanopyrimidine derivative of above 1, or a pharmaceutically acceptable salt thereof, wherein R²is a methylene group, R³ is hydrogen or lower alkyl.

3. The 4-amino-5-cyanopyrimidine derivative of above 1, or a pharmaceutically acceptable salt thereof, wherein R¹is lower alkylcarbonyl, R² is a methylene group and R³ means group (3) or group (6).

4. The 4-amino-5-cyanopyrimidine derivative of above 2, or a pharmaceutically acceptable salt thereof, wherein R⁴ is lower alkylene, and Z¹ is any of the substituents selected from the group consisting of (a2), (a14), (a15), (a28), (a32), and (a37).

5. The 4-amino-5-cyanopyrimidine derivative of above 1, or a pharmaceutically acceptable salt thereof, wherein R¹is lower alkylcarbonyl, R² is a methylene group, and R³ means group (4), group (5) or group (7) in which Z¹is lower alkoxycarbonyl or hydrogen.

6. The 4-amino-5-cyanopyrimidine derivative of above 1, or a pharmaceutically acceptable salt thereof, wherein R¹is lower alkylcarbonyl, R² is a methylene group, and R³ means group (8).

7. The 4-amino-5-cyanopyrimidine derivative of above 1, or a pharmaceutically acceptable salt thereof, wherein R¹is hydrogen or lower alkylcarbonyl, R² is a methylene group and R³ means group (9), group (10), or group (11).

8. The 4-amino-5-cyanopyrimidine derivative of above 1, or a pharmaceutically acceptable salt thereof, wherein R¹is hydrogen or lower alkylcarbonyl, R² is a methylene group and R³ means group (9), group (10), or group (11) in which Z³ means (c1), (c2), (c4), (c5), (c6), (c7), (c8), (c10), (c11), (c15), (c16), (c18), ( c21), or (c22).

9. The 4-amino-5-cyanopyrimidine derivative of above 1, or a pharmaceutically acceptable salt thereof, wherein R¹is an acetyl group, R² is a methylene group, and R³means the group (9) in which Z³ means (c4), (c5), (c6), (c10), (c11), (c16), (c18), (c21), or (c22).

Ten. The 4-amino-5-cyanopyrimidine derivative according to above 1-9, or a pharmaceutically acceptable salt thereof, which is a compound selected from the group consisting of the following 1) -19):

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-ylmethylsulfanyl) pyrimidine -4-yl] -phenyl} -acetamide,

4) N- [4- (6-amino-5-cyano-2- {6- [3- (4-methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) -phenyl] acetamide .

5) 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl) propionamide,

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-cyano-pyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminopropyl) -N-methylpropionamide,

8) 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyano-pyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-methylpiperidin-1-ylethyl) propionamide,

9) 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyano-pyrimidin-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-methylpiperidin-4-yl) propionamide,

11) N- (4- {6-amino-2- [6- (3- [1,4 '] bipiperidinyl-1'-yl-3-oxo-propyl) pyridin-2-ylmethylsulfanyl] -5-cyanopyrimidin-4-yl} phenyl) acetamide

12) N- [4- (6-amino-5-cyano-2- {6- [3-oxo-3- (2-piperidin-1-yl-methylmorpholin-4-yl) propyl] pyridin-2-ylmethylsulfanyl} - pyrimidin-4-yl) -phenyl] -acetamide,

13) N- {4- [6-amino-5-cyano-2- (6- {3- [2- (4-ethylpiperazinyl-ylmethyl) morpholin-4-yl] -3-oxopropyl} pyridin-2-methylmethylsulfanyl ) 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-ylmethylsulfanyl) -pyrimidin-4-yl] phenyl} acetamide,

15) N- {4- [6-amino-5-cyano-2- (6- {3- [4- (2-diisopropylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidine -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-yl-methylsulfanyl) 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-ylmethylsulphyl) fanyl) -pyrimidin-4-yl] phenyl} acetamide, and

19) N- [4- (6-amino -5-cyano-2- {6- [3- (4-methyl- [1,4] diazepan-1-yl) -3-oxopropyl] pyridin-2 -ylometylosulfanylo} pyrimidin-4-yl) -phenyl] -acetamide.

11. The A2a adenosine receptor agonist containing any of the 4-amino-5-cyanopyrimidine derivatives as defined in the above 1 to 10, or a pharmaceutically acceptable salt thereof as an active ingredient.

12. An intraocular pressure reducing agent comprising any of the 4-amino-5-cyanopyrimidine derivatives as defined in the above 1 to 10, or a pharmaceutically acceptable salt thereof as an active ingredient.

13. A medicament for the treatment of ocular hypertension or glaucoma, comprising any of the 4-amino-5-cyanopyrimidine derivatives as defined in the above 1 to 10, or a pharmaceutically acceptable salt thereof as an active ingredient.

The 4-amino-5-cyanopyrimidine derivative of the invention has the following structural feature, i.e., it has a pyrimidine structure, the benzene ring with a specific substituent is substituted at the 6-position of the pyrimidine ring, and the pyridine ring is substituted at the 2-position of the pyrimidine ring by a sulfanylalkylene chain , or furthermore the pyrimidine ring has a particular substituent. Based on this structural feature, the compounds of the invention have an adenosine A2a receptor activating effect, that is, a noticeable pharmacological property of the adenosine A2a agonist activity. Until now, compounds having such an original structural feature were not known and it was not predictable, based on the state of the art, that the compounds may exert some pharmacological effect.

Compounds of the invention

The term "lower alkyl" as used herein means a straight or branched chain alkyl group having 1 to 6 carbon atoms, i.e., C_1-6 straight or branched chain alkyl group.

The terms "lower alkoxy" and "lower alkylene" also means an alkoxy group and a straight chain or branched alkylene group containing 1 to 6 carbon atoms.

The terms "lower alkenyl", "lower alkenylene" and "lower alkynylene" mean an alkenyl, alkenylene and alkynylene group with a straight or branched chain containing 2 to 6 carbon atoms, respectively, group C_2-6 alkenyl, alkenylene and alkynylene with a straight or branched chain, respectively.

The term "aryl" means a monovalent group containing a monocyclic or multi-cyclic aromatic hydrocarbon, including, for example, a phenyl and naphthyl group.

piperazine, dioxolanyl,

The term "heteroaryl" means a monovalent group containing a 5 to 6-membered aromatic heteromonocyclic group having one or more, especially 1 to 3, the same or different heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or an aromatic heterocyclic group consisting of the above heteromonocyclic condensed with an aryl group such as furyl, thienyl, thiazolyl, imidazolyl, pyrazolyl, benzofuryl, indolyl, benzothiazolyl, pyridyl, pyrazinyl etc.

The term "saturated heterocycle" means a 5 to 7-membered saturated heterocycle having one or more, especially 1-3 same or different heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A saturated heterocycle is contained as a monovalent saturated heterocyclic group in any substituent, for example pyrrolidinyl, pyrrolidine, piperidyl, piperidine, piperazinyl,

1,4-diazepan-1-yl, tetrahydrotienyl, tetrahydrofuryl, 1,3-morpholinyl, morpholino, etc. are mentioned. For example, in an alkyl group having a saturated tetrahydroimidazolyl lower heterocycle case, lower alkyl is a lower alkyl group substituted by a saturated heterocycle mentioned above dihydroisoindolyl ring, a lower alkyl group substituted by a saturated heterocycle, the bond is not limited, i.e., it can be bonded to the lower an alkyl group on a nitrogen atom which is a heteroatom contained in a heterocycle or on its carbon atom. In addition, the above-mentioned 5- to 7-membered saturated heterocyclic group can be fused with an additional 1 or 2 benzene rings. Such condensed groups include, e.g., dihydroindolyl, tetrahydroquinolyl, tetrahydroquinoline, benzomorpholinyl, benzomorpholine, etc.

Below is individually illustrated each group contained in the compounds of the invention defined by the above-mentioned general formula (1). The definitions of each group listed below are adapted not only to the compounds represented by the formula (1), but also to other compounds present herein.

Examples of a lower alkylcarbonyl group indicated as R¹ include acetyl, propanoyl, butanoyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl, isopropylcarbonyl and the like, preferably acetyl and propanoyl.

Examples of the lower alkenylcarbonyl group shown as

R include acryloyl, methacryloyl, crotonoyl, isoconoyl etc., preferably acryloyl.

Examples of a lower alkoxycarbonyl group shown as R¹ include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, n-butoxycarbonyl and the like, preferably methoxycarbonyl.

Examples of the lower alkylene group shown as R²include methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene as well as their structural isomers such as 1-methylethylene. Among them, a methylene group is preferred.

Examples of a lower alkyl group shown as R³include methyl, ethyl, propyl, butyl, pentyl and hexyl as well as their structural isomers such as isopropyl. Among them, methyl is preferred.

Examples of the lower alkylene group shown as R⁴include methylene, ethylene, trimethylene, tetramethylene, heptamethylene and hexamethylene as well as their structural isomers such as 1-methylethylene. Lower alkylene group shown as R⁴ it is preferably methylene or ethylene when R³ is a group (3); lower alkylene group shown as R⁴ preferably methylene when the R group³ is group (6) or group (8);

lower alkylene group shown as R⁴ preferably ethylene or tetramethylene when the R group³ is a group (9).

Examples of a lower alkyl group shown as R⁵ include methyl, ethyl, propyl, butyl, pentyl and hexyl as well as their structural isomers such as isopropyl. Among them, methyl is preferred.

Examples of the lower alkenylene group shown as R⁶ include a simple lower alkenylene group such as ethenylene, propenylene, butenylene, pentenylene, hexenylene and butanedienylene, and their structural isomers such as 2-methylpropenylene. Among them, etheylene is preferred.

Examples of the lower alkynylene group shown as R⁷ include the straight chain of the lower alkynylene group such as ethynylene, propynylene, butynylene, pentynylene, hexinylene and butanedinylene, and their structural isomers such as 3-methylbutynylene. Among them, butynylene is preferred.

Examples of a lower alkyl group shown as R⁸ include methyl, ethyl, propyl, butyl, pentyl and hexyl as well as their structural isomers such as isopropyl. Among them, ethyl is preferred.

Examples of a lower alkyl group (a1) shown as Z¹ include a straight chain lower alkyl group such as methyl, ethyl, propyl, butyl, pentyl and hexyl as well as their structural isomers such as isopropyl. Among them, C is preferred_1-4 alkyl.

a2) shown as Z¹

An aryl lower alkyl group means a lower alkyl group substituted with an aryl group. Examples include benzyl, phenethyl, phenylpropyl, naphthylmethyl etc. Among them, a benzyl or phenethyl group is preferred.

The aminoaryl lower alkyl group (a3) ​​shown as Z¹ is an aryl-lower alkyl group substituted with an amino group on its aryl group. For example, aminobenzyl, aminophenethyl, aminophenylpropyl, aminonaphthylmethyl and the like are mentioned. Among them, aminobenzyl or aminophenethyl is preferable.

Aryl-lower alkenyl group (a4) shown as Z¹is a lower alkenyl group substituted with an aryl group. For example, phenylethenyl, phenylpropenyl, phenyl butenyl and the like are mentioned. Among them, a phenyl propenyl group is preferred.

Heteroaryl lower alkyl group (a5) shown as Z¹is a lower alkyl group substituted with a heteroaryl group. For example, furylmethyl, pyrazolylethyl, imidazolylpropyl, pyridylmethyl and the like are mentioned. Among them, furylmethyl or pyridylmethyl group is preferred.

The heteroaryl lower alkenyl group (a6) shown as

FROM¹ is a lower alkenyl group substituted with a heteroaryl group. For example, pyridylethenyl, pyridylpropenyl, furylpropenyl and the like are mentioned. Among them are preferred pyridylpropenyl or furylpropenyl groups.

Heteroaryl lower alkyl group (a7) shown as Z¹ is aryl-lower alkyl substituted with a heteroaryl group on its aryl group. Examples are furylphenylmethyl, thienylphenylethyl, pyridylphenylpropyl, triazolylphenylmethyl, imidazolylphenylmethyl and the like. Among them, triazolylphenylmethyl or imidazolylphenylmethyl are preferable.

Examples of the hydroxy-lower alkyl group (a8) shown as Z¹ include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,

1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl etc., preferably 3-hydroxypropyl and 4-hydroxybutyl.

Examples of the aryloxy lower alkyl group (a9) shown as Z¹ include phenoxymethyl, 1-phenoxyethyl, 2-phenoxyethyl, 1-phenoxypropyl, 2-phenoxypropyl, 3-phenoxypropyl etc., preferably 3-phenoxypropyl.

Examples of the amino-lower alkyl group (a10) shown as Z¹ include aminomethyl, 1-aminoethyl, 2-aminoethyl, 1 aminopropyl, 2-aminopropyl, 3-aminopropyl etc., preferably 2 aminoethyl and 3-aminopropyl.

Examples of the aminocarbonyl lower alkyl group (a11) shown as Z¹ include aminocarbonylmethyl, 1aminocarbonylethyl, 2-aminocarbonylethyl, 1-aminocarbonylpropyl, 2-aminocarbonylpropyl, 3-aminocarbonylpropyl and the like, preferably aminocarbonylmethyl.

Lower alkylcarbonyl (a12) shown as Z¹includes acetyl, propanoyl, propylcarbonyl, butylcarbonyl, pentylcarbonyl, hexylcarbonyl, isopropylcarbonyl etc., preferably acetyl and propanoyl.

Examples of a lower alkoxy-lower alkylcarbonyl group (a13) shown as Z¹ include methoxymethylcarbonyl, methoxyethylcarbonyl, ethoxyethylcarbonyl and the like, preferably methoxymethylcarbonyl.

Examples of the amino-lower alkylcarbonyl group ((a14) and (b3)) shown as Z¹ and Z² include aminomethylcarbonyl, aminoethylcarbonyl, aminopropylcarbonyl, aminobutylcarbonyl and the like, preferably aminomethylcarbonyl and aminoethylcarbonyl.

Examples of the arylcarbonyl group (a15) shown as Z¹include benzoyl, naphthylcarbonyl etc., preferably benzoyl.

Examples of the aryl lower alkylcarbonyl group (a16) shown as Z¹ include benzylcarbonyl, naphthylmethylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, phenylbutylcarbonyl and the like, preferably benzylcarbonyl and phenethylcarbonyl.

Examples of the aryl-lower alkenylcarbonyl group (a17) shown as Z¹ include phenylethenylcarbonyl, phenylpropylcarbonyl, phenylbutenylcarbonyl and the like, preferably phenylethenylcarbonyl.

Examples of the aryloxy-lower alkylcarbonyl group (a18) shown as Z¹ include phenoxymethylcarbonyl, phenoxyethylcarbonyl, phenoxypropylcarbonyl, phenoxybutylcarbonyl and the like, preferably phenoxymethylcarbonyl and phenoxyethylcarbonyl.

Examples of the heteroarylcarbonyl group (a19) shown as Z¹ include furylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, thiazolylcarbonyl, pyridylcarbonyl, quinolylcarbonyl and the like, preferably pyridylcarbonyl, furylcarbonyl and thienylcarbonyl.

Examples of the heteroaryl lower alkylcarbonyl group (a20) shown as Z¹ include furylmethylcarbonyl, furylethylcarbonyl, thienylmethylcarbonyl, pyridylmethylcarbonyl, pyridylethylcarbonyl, pyridylpropylcarbonyl and the like, preferably thienylmethylcarbonyl and pyridylmethylcarbonyl.

Examples of the heteroaryl lower alkenylcarbonyl group (a21) shown as Z¹ include pyridylacryloyl, imidazolylacryloyl etc., preferably pyridylacryloyl.

Examples of the heteroaryloxy-lower alkylcarbonyl group (a22) shown as Z¹ include pyridyloxymethylcarbonyl, quinolyloxyethylcarbonyl, tetrahydroquinolinonyloxymethylcarbonyl, tetrahydroquinolinonyloxypropylcarbonyl and the like, preferably tetrahydroquinolinyloxymethylcarbonyl and tetrahydroquinolinyloxypropylcarbonyl.

Examples of heteroarylsulfanyl-lower alkylcarbonyl group (a23) shown as Z¹ include furylsulfanylmethylcarbonyl, pyridylsulfanylethylcarbonyl, quinolylsulfanylpropylcarbonyl and the like, preferably pyridylsulfanylmethylcarbonyl.

Examples of the heteroarylarylcarbonyl group (a24) shown as Z¹ include pyrrolylphenylcarbonyl, pyrazolylphenylcarbonyl, imidazolylphenylcarbonyl, triazolylphenylcarbonyl, thienylphenylcarbonyl, furylphenylcarbonyl, pyridylphenylcarbonyl and the like, preferably pyrrolylphenylcarbonyl, pyrazolylphenylcarbonyl and imidazylcarbonylphenyl

Examples of the arylsulfanyl-lower alkylcarbonyl group (a25) shown as Z¹ include phenylsulfanylmethylcarbonyl, phenylsulfanylethylcarbonyl, phenylsulfanylpropylcarbonyl and the like, preferably phenylsulfanylmethylcarbonyl.

Examples of the arylcarbonyl-lower alkylcarbonyl group (a26) shown as Z¹ include benzoylmethylcarbonyl, benzoylethylcarbonyl, benzoylpropylcarbonyl and the like, preferably benzoylethylcarbonyl.

Examples of the arylamino-lower alkylcarbonyl group (a27) shown as 2¹ include phenylaminomethylcarbonyl, phenylaminoethylcarbonyl, phenylaminopropylcarbonyl etc., preferably phenylaminomethylcarbonyl.

Examples of the lower alkoxycarbonyl group ((a28) and (b2)) shown as Z¹ and Z² include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, isopropoxycarbonyl etc. Among these, methoxycarbonyl and t-butoxycarbonyl are preferred.

Examples of the lower alkylsulfonyl group ((a29) and (b8)) shown as Z¹ and Z² include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc. Among them, a preferred lower alkylsulfonyl group (a29) shown as Z¹ is methylsulfonyl or ethylsulfonyl; and a preferred lower alkylsulfonyl group (b8) shown as Z² is ethylsulfonyl or propylsulfonyl.

Examples of the arylsulfonyl group (a30) shown as Z¹include phenylsulfonyl, toluenesulfonyl, naphthalenesulfonyl and the like, preferably phenylsulfonyl.

Examples of the heteroarylsulfonyl group (a31) shown as Z¹ include furylsulfonyl, thienylsulfonyl, pyridylsulfonyl, imidazolylsulfonyl and the like, preferably imidazolylsulfonyl.

Lower alkyl substituted with saturated heterocycle (a33) shown as Z¹ is a lower alkyl group substituted with a saturated heterocyclic group. Examples are pyrrolidinoethyl, piperidinoethyl, piperidyl ethyl, morpholinoethyl, morpholinylmethyl etc., preferably piperidinoethyl and morpholinoethyl.

A carbonyl-lower alkyl group substituted with a saturated heterocycle (a34) shown as Z¹ is a carbonyl-lower alkyl group substituted with a saturated heterocyclic group. For example, pyrrolidinecarbonylethyl, piperidinecarbonylethyl, piperidylcarbonylethyl, morpholinocarbonylethyl, morpholinylcarbonylmethyl and the like are shown, preferably piperidinecarbonylmethyl.

Aryl-lower alkyl substituted with saturated heterocycle (a35) shown as Z¹ is an aryl-lower alkyl group substituted with a saturated heterocyclic group on the aryl ring. Examples are shown pyrrolidinophenylethyl, piperidinophenylmethyl, piperidylphenylethyl, morpholinophenylethyl, morpholinylphenylmethyl, piperazinophenylmethyl etc., preferably piperazinophenylmethyl.

Examples of the carbonyl group substituted with saturated heterocycle ((a36) and (b7)) shown as Z¹ and Z² include pyrrolidinecarbonyl, piperidinecarbonyl, piperidinylcarbonyl, morpholinocarbonyl, morpholinylcarbonyl, piperazinocarbonyl, piperazinylcarbonyl, thiazolylcarbonyl, pyrrolylcarbonyl and the like, preferably piperazinecarbonyl, thiazolylcarbonyl and pyrrolylcarbonyl.

Examples of the lower alkylcarbonyl group substituted with saturated heterocycle ((a37) and (b5)) shown as Z¹ and Z² include pyrrolidinylethylcarbonyl, piperidinylmethylcarbonyl, piperidinylethylcarbonyl, piperidylmethylcarbonyl, morpholinoethylcarbonyl, morpholinylmethylcarbonyl, piperazinomethylcarbonyl, piperazinylpropylcarbonyl, thiazolylmethylcarbonyl and the like, preferably piperazinylmethylphenyl

Examples of the substituted arylcarbonyl group substituted with saturated heterocycle (a38) shown as Z¹ include pyrrolidinophenylcarbonyl, piperidinophenylcarbonyl, piperidylphenylcarbonyl, morpholinophenylcarbonyl, morpholinylphenylcarbonyl, thiomorpholinophenylcarbonyl, piperazinophenylcarbonyl and the like, preferably pyrrolidinophenylcarbonyl, morpholinylphenylcarbonyl and thiomorpholinophenylcarbonyl.

Examples of the optional substituent contained in each group as part of the group shown as the above Z¹ are listed as follows:

Examples of lower alkyl include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl etc. Among them, methyl, ethyl and isopropyl are preferred.

Examples of the lower alkylcarbonyl group include acetyl, propanoyl, butanoyl, butylcarbonyl, pentylcarbonyl etc., preferably acetyl.

Examples of the halogen atom include fluorine, chlorine, bromine, and iodine, preferably fluorine and chlorine.

Examples of the lower alkoxy group include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, isopropoxy etc. Among them, C_1-4 alkoxy is preferred.

Examples of the halogen-lower alkoxy group include chloromethoxy, dichloromethoxy, trichloromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy etc., preferably trifluoromethoxy.

Examples of the aryl group include phenyl, naphthyl etc., preferably phenyl.

Examples of the aryloxy group include phenoxy, naphthoxy and the like, preferably phenoxy.

Examples of the dihalomethylenedioxy group include difluoromethylenedioxy, dichloromethylenedioxy and the like, preferably difluoromethylenedioxy.

Examples of the lower alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl and the like, preferably methoxycarbonyl.

Examples of the lower alkylcarbonyloxy group include acetoxy, propylcarbonyloxy and the like, preferably acetoxy.

Examples of the lower alkylamino group include mono or di (lower alkyl) amino such as methylamino, dimethylamino, diethylamino, diisopropylamino and the like, preferably dimethylamino.

Examples of the lower alkylcarbonylamino group include acetylamino, propionylamino and the like, preferably acetylamino.

Examples of the hydroxy-lower alkyl group include a lower alkyl group substituted with one hydroxyl group such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylethyl and the like, preferably hydroxymethyl or 2-hydroxyethyl .

Examples of the halogen-lower alkyl group include a lower alkyl group having 1 to 5 halogen atoms, such as chloroethyl, dichloromethyl, trifluoromethyl, pentafluoroethyl etc., preferably trifluoromethyl.

Examples of the haloaryl group include chlorophenyl, dichlorophenyl, fluorophenyl, difluorophenyl, pentafluorophenyl, bromophenyl, iodophenyl, chloronaphthyl and the like, preferably chlorophenyl.

Examples of the lower alkylsulfanyl group include methylsulfanyl, ethylsulfanyl, propylsulfanyl and the like, preferably methylsulfanyl.

Examples of the amino group substituted with 1 or 2 lower alkyl groups that are included as part of the aminoaryl-lower alkyl group (a3), the amino-lower alkyl group (a10), the aminocarbonyl lower alkyl group (a11) or the amino-lower alkylcarbonyl group ( a14), include dimethylaminophenyl ethyl, dimethylaminoethyl, diethylaminoethyl, diisopropylaminoethyl, dimethylaminocarbonylmethyl, diethylaminomethylcarbonyl, diethylaminoethylcarbonyl etc. In addition, examples of the above amino group substituted with one carbonyl group include N-formylaminomethylcarbonyl, and examples of the above amino group substituted with one lower alkylcarbonyl group include acetylaminomethylcarbonyl.

Examples of the halogen substituted aryl group (s) where the aryl group is included as part of the aryl lower alkyl (a2), arylcarbonyl (a15), aryl lower alkylcarbonyl (a16), aryl lower alkenylcarbonyl (a17), aryloxy-lower alkylcarbonyl ( a18), arylsulfonyl (a30) and aryl-lower alkyl having a saturated heterocycle (a35), include chlorophenylcarbonyl, dichloro (aminosulfonyl) phenylcarbonyl, chlorophenylmethylcarbonyl and fluoro (4-methylpiperazine) phenylmethyl. Examples of the aryl group substituted with a hydroxyl group (we) include hydroxyphenylmethyl. Examples of the aryl group substituted with a lower alkyl group (s) include methylphenylcarbonyl, methylphenylmethylcarbonyl, methylphenoxymethylcarbonyl and methylphenylsulfonyl. Examples of the aryl group substituted by the lower alkoxy group include methoxyphenylmethyl, trimethoxyphenylmethyl, butoxyphenylmethyl, ethoxyphenylmethyl, methoxyphenylcarbonyl, methoxyphenylmethylcarbonyl, methoxyphenoxymethylcarbonyl and methoxyphenylsulfonyl. Examples of the aryl group substituted with a halogeno lower alkoxy group include trifluoromethoxyphenylmethylcarbonyl. Examples of the aryl group substituted with another aryl group include biphenyl. Examples of the aryl group substituted with aryloxy include phenoxyphenylmethyl and phenoxyphenylcarbonyl. Examples of the aryl group substituted with methylenedioxy include methylenedioxyphenylmethyl and methylenedioxyphenylcarbonyl. Examples of the aryl group substituted with dihalomethylenedioxy include difluoromethylenedioxyphenylmethyl. Examples of the carboxy substituted aryl group include hydroxycarbonylphenylmethyl. Examples of the aryl group substituted with lower alkoxycarbonyl include methoxycarbonylphenylmethyl and methoxycarbonylphenylcarbonyl. Examples of the aryl group substituted with lower alkylcarbonyloxy include methylcarbonyloxyphenylmethyl and methylcarbonyloxyphenylcarbonyl. Examples of the aryl group substituted by the nitro group (s) include nitrophenylcarbonyl. Examples of the aryl group substituted by the lower alkylamino group (e) include dimethylaminophenylcarbonyl and dimethylaminophenylethenecarbonyl. Examples of the aryl group substituted by the lower alkylcarbonylamino group (e) include acetylaminophenylcarbonyl. Examples of the aryl group substituted with the aminosulfonyl group (s) include dichloro (aminosulfonyl) phenylcarbonyl.

Examples of the heteroaryl group substituted by the halogen atom (s) where the heteroaryl group is included as part of a heteroaryl lower alkyl (a5), heteroarylcarbonyl (a19), heteroaryl lower alkylcarbonyl (a20), heteroaryl lower alkenylcarbonyl (a21) group, heteroaryloxy-lower alkenylcarbonyl (a22), heteroarylsulfanyl-lower alkylcarbonyl (a23), heteroarylarylcarbonyl (a24) and heteroarylsulfonyl (a31), include a chlorothienylmethyl group, dichloroimidazolylmethyl and chloro- (hydroxy) pyridylcarbonyl. Examples of the heteroaryl group substituted with the hydroxyl group (s) include hydroxypyridylcarbonyl and chloro (hydroxy) pyridylcarbonyl. Examples of the heteroaryl group substituted with a lower alkyl group include methylthiazolylmethyl, n-hexyl-tetrazolylmethyl, methylisoxazolylmethyl and methylimidazolylmethyl. Examples of the heteroaryl group substituted with a hydroxy-lower alkyl group include hydroxymethylpyridylmethyl. Examples of the heteroaryl group substituted with a halogen-lower alkyl group include trifluoromethylbenzofuranylmethyl. Examples of the heteroaryl group substituted with the aryl group include phenylthiazolylmethyl and phenylimidazolylmethyl. Examples of the heteroaryl group substituted with the haloaryl group (s) include chlorophenylpyrrolylmethyl. Examples of the heteroaryl group substituted with a lower alkylsulfanyl group (e) include methylsulfanylpyridylcarbonyl. Examples of the heteroaryl group substituted with the aminocarbonyl group (e) include aminocarbonylpyrazolylcarbonyl. Examples of the heteroaryl group substituted with the carboxy group (e) include hydroxycarbonylfurylmethyl and hydroxycarbonylthienylmethyl.

The saturated heterocycle moiety incorporated as part of the groups described in (a33) - (a38) may have a specific substituent on its nitrogen atom or carbon atom (lower alkyl or lower alkoxycarbonyl as a substituent on a nitrogen atom and an oxo group as a substituent on a carbon atom). Examples of preferred groups in the above-mentioned are as follows.

Examples of the lower alkyl group substituted with saturated heterocycle (a33), which is further substituted with the lower alkyl group on the nitrogen of the heterocycle, are groups

<img file="PL1740574T3_D0001.tif" />

and the like, in which Me is methyl, the same as below.

Examples of the aryl lower alkyl group substituted with saturated heterocycle (a35) which is further substituted with one lower alkyl group on the nitrogen atom in the heterocycle

Me

<img file="PL1740574T3_D0002.tif" />

and similar.

Examples of the carbonyl group substituted with saturated heterocycle (a36), which is further substituted with a lower alkylcarbonyl group on the nitrogen atom of the heterocycle,

<img file="PL1740574T3_D0003.tif" />

<img file="PL1740574T3_D0004.tif" />

etc., where Ac is acetyl, the same as shown below.

Examples of the carbonyl group substituted with saturated heterocycle (a36), which is further substituted with one oxo group on a carbon atom in a heterocycle, include

<img file="PL1740574T3_D0005.tif" />

e.t.c.

Examples of the lower alkylcarbonyl group substituted with saturated heterocycle (a37), which is further substituted with one lower alkyl at the nitrogen of the heterocycle, include

N

<img file="PL1740574T3_D0006.tif" />

Me and the like.

Examples of the lower alkylcarbonyl group substituted with saturated heterocycle (a37), which is further substituted with two oxo groups on carbon atoms in the heterocycle, include and the like.

Examples of the arylcarbonyl group substituted with saturated heterocycle (a38) which is further substituted with one oxo group on a carbon atom in a heterocycle include

<img file="PL1740574T3_D0007.tif" />

and similar.

Among each group (b1) - (b7) shown as Z², (b2), (b3), (b5) and (b7) are mentioned above.

Examples of a lower alkenylcarbonyl group (b4) shown as Z² include acryloyl, methacryloyl, crotonoyl, isoconoyl etc., preferably acryloyl.

Examples of the piperidine-lower alkylcarbonyl group substituted with saturated heterocycle (b6) shown as Z² include pyrrolidinopiperidine methylcarbonyl, pyrrolidinylpiperidineethylcarbonyl, piperidinopiperidinylmethylcarbonyl, piperidylpiperidineethylcarbonyl, morpholinopiperidineethylcarbonyl, piperazinopiperidinepropylcarbonyl etc., preferably a group

<img file="PL1740574T3_D0008.tif" />

and similar.

Examples of a lower alkyl group which is optionally substituted in the amino group included as part of the group (b3) shown as Z² include methyl, ethyl, propyl, butyl, pentyl or hexyl and their structural isomers such as isopropyl. Among them, methyl, ethyl and isopropyl are preferred. In addition, examples of the lower alkyl group which is optionally substituted on the nitrogen atom of the saturated heterocyclic group included in each (b5) - (b7) group are also the same as above. Preferably, examples of the amino group substituted with said lower alkyl group and the group substituted with a saturated heterocycle that is substituted with said lower alkyl group on a nitrogen atom include dimethylaminomethylcarbonyl and 4-methylpiperazinecarbonyl, respectively.

Examples of the lower alkoxy group (c2) shown as

FROM³ include methoxy, ethoxy, t-butoxy, n-butoxy etc., preferably ethoxy and t-butoxy.

Examples of the amino-lower alkylamino group (c4) indicated as Z³ include aminomethylamino, aminoethylamino, aminopropylamino, aminobutylamino and the like, preferably aminoethylamino and aminopropylamino.

Examples of the amino-lower alkylpiperazine group (c6) indicated as Z³ include aminomethyl piperazine, aminoethyl piperazine, aminopropyl piperazine, aminobutyl piperazine and the like, preferably aminoethyl piperazine and aminopropyl piperazine.

Examples of the aminocarbonyl lower alkylpiperazine group (c7) indicated as Z³ include aminocarbonyl methyl piperazine, aminocarbonyl ethyl piperazine, aminocarbonyl propyl piperazine, aminocarbonyl butyl piperazine etc., preferably aminocarbonyl methyl piperazine.

Examples of the amino-lower alkyl-1,4-diazepan-1-yl group (c9) indicated as Z³ include aminomethyl-1,4-diazepan-1-yl, aminoethyl-1,4-diazepan-1-yl, aminopropyl-1,4-diazepan-1-yl, aminobutyl-1,4-diazepan-1-yl and the like, preferably aminopropyl -1,4-diazepan-1-yl.

Examples of the amino-lower alkylaminopiperidine (c12) group indicated as Z³ include aminomethylaminopiperidine, aminoethylaminopiperidine, aminopropylaminopiperidine, amino-butylaminopiperidine and the like, preferably aminoethylaminopiperidine.

Examples of the amino-lower alkylpiperidine (c13) group indicated as Z³ include aminomethylpiperidine, aminoethylpiperidine, aminopropylpiperidine, aminobutylpiperidine and the like, preferably aminoethylpiperidine.

Examples of the amino substituted group substituted with saturated heterocycle (c15) indicated as Z³ include piperidinoamino, piperidylamino, piperazineamino, piperazinylamino, pyrrolidinylamino, morpholinylamino and the like, preferably piperidinoamino and piperazineamino.

Examples of lower alkylamino substituted with saturated heterocycle (c16) indicated as Z³ include piperidinoethylamino, piperidylmethylamino, pyrrolidinoethylamino, morpholinopropylamino, piperazinopropylamino and the like, preferably piperidinoethylamino.

Examples of the saturated piperazine substituted piperazine group (c17) shown as Z³ include piperidyl-piperazine, morpholinyl-piperazine, etc., preferably piperidyl-piperazine.

Lower alkylpiperazine substituted with saturated heterocycle (c18) indicated as Z³ is a lower alkylpiperazine group substituted by a saturated heterocyclic group on its lower alkyl group. Examples include a pirolidynoetylopiperazynową, morpholinoethylpiperazino, piperydynoetylopiperazynową, piperydyletylopiperazynową, piperidylmethylpiperazino, 1,3-dioksolanylometylopiperazynową, tetrahydrofurylometylopiperazynwą etc., Preferably pirolidynoetylopiperazynową, morpholinoethylpiperazino, piperydynoetylopiperazynową, piperidylmethylpiperazino.

Examples of a carbonyl-lower alkylpiperazine group substituted with a saturated heterocycle (c19) indicated as Z³include pyrrolidinecarbonylmethylpiperazine, piperidinecarbonylethylpiperazine and the like, preferably pyrrolidinecarbonylmethylpiperazine.

Examples of the lower alkyl-1,4-diazepan-1-yl group substituted with a saturated heterocycle (c20) shown as Z³include morpholinopropyl-1,4-diazepan-1-yl, piperidinoethyl-1,4-diazepan-1-yl and the like, preferably morpholinopropyl-1- 4-diazepan-1-yl.

Examples of the piperidine group substituted with saturated heterocycle (c21) shown as Z³ include piperidinopiperidine, piperazinopiperidine, morpholinopiperidine, morpholinylpiperidine and the like, preferably piperidinopiperidine and piperazinopiperidine.

Examples of the lower alkyl morpholine group substituted with saturated heterocycle (c22) indicated as Z³ include piperidinomethylmorpholine, piperazinomethylmorpholine,

1,4-diazepan-1-ylmethylmorpholine and the like, preferably piperidinomethylmorpholine and piperazinomethylmorpholine.

Preferable examples of the amino (c3) and amino groups included as part of the lower amino-alkylamino (c4), amino-lower alkylpiperazine (c6), aminocarbonyl lower alkylpiperazine (c7) amino-lower alkyl-1,4-diazepan-1-yl (c9) group , aminopiperidine (c11), amino-lower alkylaminopiperidine (c12), amino-lower alkylpiperidine (c13), amino substituted with saturated heterocycle (c15) and lower alkylamino group substituted with saturated heterocycle (c16), which are substituted with 1-2 substituents selected from the group consisting of a lower alkyl group, hydroxy-lower alkyl group, aryl group, heteroaryl group, aryl lower alkyl group, alkoxyaryl lower alkyl group, heteroaryl lower alkyl group, lower alkylcarbonyl and lower alkoxycarbonyl, are shown below.

Me

Me

<img file="PL1740574T3_D0009.tif" />

<img file="PL1740574T3_D0010.tif" />

<img file="PL1740574T3_D0011.tif" />

OH

OH

<img file="PL1740574T3_D0012.tif" />

Me

<img file="PL1740574T3_D0013.tif" />

Me

Me

<img file="PL1740574T3_D0014.tif" />

Me

<img file="PL1740574T3_D0015.tif" />

et

N

et

<img file="PL1740574T3_D0016.tif" />

<img file="PL1740574T3_D0017.tif" />

<img file="PL1740574T3_D0018.tif" />

N

et

<img file="PL1740574T3_D0019.tif" />

ph

<img file="PL1740574T3_D0020.tif" />

<img file="PL1740574T3_D0021.tif" />

Me

N

Me

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

Preferable examples of the amino group included as part of the aminopiperidine (c11) group which is substituted by an aryl lower alkylcarbonyl group are shown below.

About Ph

About Ph

N

<img file="PL1740574T3_D0022.tif" />

Me

Preferable examples of the piperazine (c5) and 1,4-diazepan-1-yl (c8) group which have any of the substituents selected from the group consisting of a lower alkyl group, a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aryl group, a lower group alkylaryl, hydroxyaryl group, cyanoaryl group, haloaryl group, aryl lower alkyl group, lower alkoxyaryl lower alkyl group, haloaryloxy lower alkyl group, heteroaryl group, lower alkylheteroaryl group, halogen-lower alkylheteroaryl group, cyanoheteroaryl group, heteroaryl lower alkyl group, lower alkoxycarbonyl group and lower alkylcarbonyl group in the 4-position

<td>shadow</td><td>are shown</td><td>below.</td>

<td>-Γ</td><td>NMe NMe</td><td>-Ο</td>

<td>ν_</td><td></td><td>^N Me</td>

<td>N</td><td>-OMe</td><td>-, ΛΛ-,</td>

<td>^N</td><td>s</td><td> \ /</td>

ph

<img file="PL1740574T3_D0023.tif" />

<img file="PL1740574T3_D0024.tif" />

<img file="PL1740574T3_D0025.tif" />

CN

<img file="PL1740574T3_D0026.tif" />

<a name="caption1"></a>Me

In the exemplified groups as shown above, OMe is a methoxy group and Ot-Bu is a tert-butoxy group (the same are shown below).

Preferable examples of the saturated heterocycle included as part of the groups in (c15) - (c22) which has any of the substituents selected from the group consisting of a lower alkyl group, an aryl group, a cyanoaryl group, a lower alkylcarbonyl group, a halogen-lower alkylaryl group and an aryl-lower group alkyl on a ring nitrogen atom are shown below.

Me

et

<img file="PL1740574T3_D0027.tif" />

N

<img file="PL1740574T3_D0028.tif" />

N

<img file="PL1740574T3_D0029.tif" />

-N \ —Ph \ /

<img file="PL1740574T3_D0030.tif" />

<img file="PL1740574T3_D0031.tif" />

CN

<img file="PL1740574T3_D0032.tif" />

Me

ph

CF3

<img file="PL1740574T3_D0033.tif" />

ph

<img file="PL1740574T3_D0034.tif" />

Preferable examples of the piperazine (c5), piperidine (c10) and saturated heterocycle groups included as part of the groups in (c15) - (c22) which have any of the substituents selected from the group consisting of a hydroxyl group, oxo group, lower alkyl group, hydroxy group - a lower alkyl, aryl, lower aryl, aminocarbonyl, and lower alkylamino group on the ring carbon atom are shown below.

OH

<img file="PL1740574T3_D0035.tif" />

<img file="PL1740574T3_D0036.tif" />

NPh

Me

<img file="PL1740574T3_D0037.tif" />

Me

<img file="PL1740574T3_D0038.tif" />

ABOUT

ph

ABOUT

<img file="PL1740574T3_D0039.tif" />

H

Preferred examples of the group having the substituent (s) selected from the group consisting of a lower alkyl group, an aryl, cyanoaryl group, a lower alkylcarbonyl group, a halogen-lower alkylaryl group and an aryl-lower alkyl group on a saturated heterocycle nitrogen atom, included as part of groups in (c15) - (c22), and preferred examples of groups having substituents selected from the group consisting of a hydroxyl group, oxo group, lower alkyl group, hydroxy lower alkyl group, aryl group, an aryl lower alkyl group, an aminocarbonyl group and a lower alkylamino group on a saturated carbon heterocycle atom are shown below.

Examples of the amino group having a saturated heterocycle (c15) which has a substituent on the heterocycle include _NH

NMe

<img file="PL1740574T3_D0040.tif" />

Leaves

Me

ph

et

N

Me

CN etc.

Examples of the lower alkylamino group substituted with saturated heterocycle (c16) that is substituted on the heterocycle include

<img file="PL1740574T3_D0041.tif" />

et

<img file="PL1740574T3_D0042.tif" />

e.t.c.

Examples of the lower piperazine group substituted with saturated heterocycle (c17) that is substituted on the heterocycle include

NN NMe etc.

Examples of the lower alkyl piperazine group substituted with a saturated heterocycle (c18) that is substituted on the heterocycle include

<img file="PL1740574T3_D0043.tif" />

Me etc.

Examples of the piperidine group substituted with a saturated heterocycle (c21) that has substituents on the heterocycle include

<img file="PL1740574T3_D0044.tif" />

e.t.c.

Examples of the lower alkyl morpholine group substituted with saturated heterocycle (c22) include

<img file="PL1740574T3_D0045.tif" />

etc., and examples of the group further substituted with a substituent on the nitrogen atom of the heterocycle include

Me etc.

Preferred compounds of the invention illustrated by the aforementioned general formula (1) may include a compound in which

R² is a methylene group and R³ represents a hydrogen atom or a lower alkyl group.

A second group of preferred compounds may include a compound wherein R¹ is a lower alkylcarbonyl group, R²is a methylene group and R³ means group (3) or group (6). Among such compounds, a more preferred compound may be a compound in which R⁴ is lower alkylene and Z¹means any group selected from (a2), (a14), (a15), (a28), (a32) and (a37).

A third group of preferred compounds may include a compound in which R¹ is a lower alkylcarbonyl group, R² is a methylene group and R³ means group (4), group (5) or group (7) provided that Z¹ is a lower alkoxycarbonyl group or a hydrogen atom.

A fourth group of preferred compounds may include a compound wherein R¹ is a lower alkylcarbonyl group, _R2 is a methylene group and R³ means group (8).

A fifth group of preferred compounds may include a compound wherein R¹ is a hydrogen atom or a lower alkylcarbonyl group, R² is a methylene group and R³ means group (9), group (10) or group (11).

A sixth group of preferred compounds may include a compound wherein R¹ is a hydrogen atom or a lower alkylcarbonyl group, R² is a methylene group and R³ means group (9), group (10) or group (11) provided that Z³means (c1), (c2), (c4), (c5), (c6), (c7), (c8), (c10), (c11), (c15), (c16), (c18), ( c21) or (c22).

A seventh group of preferred compounds may include a compound wherein R¹ is an acetyl group, R² is a methylene group and R³ means group (9) provided that Z³ means (c4), (c5), (c6), (c10), (c11), (c16), (c18), (c21) or (c22).

Examples of preferred compounds of the invention include the following compounds shown in 1) -19):

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-ylmethylsulfanyl) pyrimidine -4-yl] -phenyl} -acetamide,

4) N- [4- (6-amino-5-cyano-2- {6- [3- (4-methylpiperazin-1-yl) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) -phenyl] acetamide .

5) 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl) propionamide,

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-methyl-piperidin-1-ylethyl) propionamide,

9) 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyano-pyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2-diethyl-aminoethyl) -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-oxo-propyl) pyridin-2-ylmethylsulfanyl] -5-cyanopyrimidin-4-yl} -phenyl) -acetamide,

12) N- [4- (6-amino-5-cyano-2- {6- [3-oxo-3- (2-piperidin-1-yl-methylmorpholin-4-yl) propyl] pyridin-2-ylmethylsulfanyl} - pyrimidin-4-yl) -phenyl] -acetamide,

13) N- {4- [6-amino-5-cyano-2- (6- {3- [2- (4-ethylpiperazin-yl-methyl) morpholin-4-yl] -3-oxopropyl} pyridin-2 -ylometylosulfanylo) 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-ylmethylsulfanyl) -pyrimidin-4-yl] phenyl} acetamide,

15) N- {4- [6-amino-5-cyano-2- (6- {3- [4- (2-diisopropylaminoethyl) piperazin-1-yl] -3-oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidine -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-yl-methylsulfanyl) pyrimidin-4-yl] phenyl} acetamide,

17) N- {4- [6-amino-5-cyano-2- (6- {3- [4- (2-morpholin-4-ethylethyl) piperazin-1-yl] -3-oxopropyl} pyridinium 2-ylometylosul-phenylsulfanyl) -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-ylmethylsulphyl) fanyl) -pyrimidin-4-yl] phenyl} acetamide, and

19) 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.

Certain compounds of the invention may have the form of geometrical or tautomeric isomers due to the substituent, double bond, amide bond, etc. The present invention includes all their separate isomers and mixtures thereof.

In addition, certain compounds of the invention may have asymmetric carbon atoms, and therefore may have the form of optical isomers, due to the asymmetric carbon atoms. The present invention contains all mixtures of optical isomers and separate isomers.

Further, the present invention includes a radioisotope compound of the aforementioned compounds of the invention.

In addition, the compounds of the invention include their pharmacologically acceptable prodrugs. "Pharmacologically acceptable prodrug" means a compound containing a group (protective group) that can be converted to a group of compounds of the invention by solvolysis or physiological effects, etc. Groups that may be included in prodrugs are known (see, For example, Prog. Med. , 5, 2157-2161, 1985; and "Pharmaceutical Research and Development" Vol 7, p. 163196, 1990 Hirokawa Publishing Company). Such groups can be converted to functional groups such as -NH₂, -OH and -COOH by the above solvolysis, etc. For example, compounds of the invention having the form of an ethyl ester, such as the compound of Example 43, can be converted to a compound of the invention having the form of a carboxylic acid, i.e. the compound of Example 45 by in vivo esterase.

In addition, the compound of the invention may be prepared in the form of a salt with an acid or base according to the type of substituent. The present invention includes such a salt, especially a salt with a pharmaceutically acceptable acid and base. Acid addition salts include, for example, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, acid methanesulfonic acid, ethanesulfonic acid and glutamic acid. In addition, examples of the base used to form the salt include inorganic base such as sodium, potassium, magnesium, calcium and aluminum base; organic base such as methylamine, ethylamine, meglumine and ethanolamine; and a basic amino acid such as lysine, arginine and ornithine. Salts with a base also include an ammonium salt. Such salts can be prepared by conventional methods.

In addition, the present invention also includes a hydrate, solvate and polymorph of a compound of the invention and a pharmaceutically acceptable salt thereof.

Preparation of compounds according to the invention

In the following, the preparation of compounds of the invention is described in detail, including their pharmaceutically acceptable salts (shown below, refer to "compound (s) of the invention" unless otherwise indicated).

Compounds of the invention can be prepared according to various known methods using appropriate starting materials corresponding to their basic structure or types of substituents. Then, depending on the type of functional group in the desired compound, in manufacturing technique it can be effective when the functional group of the starting compound (or intermediate) is substituted by a suitable protecting group which is a group readily convertible to a functional group. Such functional groups include the -NH group₂, -OH, -COOH etc. Protective groups are exemplified in the textbook Greene and Wuts, "Protective Groups in Organic Synthesis" 3rd Edition, 1999 by John Wiley &amp; Sons Inc. The substitution reaction of the protecting group may be determined depending on the type of protecting group and in accordance with the reaction conditions described in the above manual. In addition, using typical processes, e.g. In the methods described in the above manual, the protective group introduced by the above substitution reaction can be cleaved from the compound after obtaining the desired compound in the appropriate reaction.

Compounds of the invention can be prepared according to the method described in Scheme 1 below.

Diagram 1

NHR¹

<img file="PL1740574T3_D0046.tif" />

OH

2a

<img file="PL1740574T3_D0047.tif" />

H 2 N

NH

<img file="PL1740574T3_D0048.tif" />

N

<img file="PL1740574T3_D0049.tif" />

N

<img file="PL1740574T3_D0050.tif" />

XR² N

2d)

R3

2c)

NHR¹

N

<img file="PL1740574T3_D0051.tif" />

(2e)

N

<img file="PL1740574T3_D0052.tif" />

(1)

<img file="PL1740574T3_D0053.tif" />

R3 (O) in which R¹, R² and R³ have the meanings defined above, provided that R¹ does not mean a hydrogen atom. X is halogen, alkylsulfonyloxy or arylsulfonyloxy.

Compounds (1) of the invention can be prepared from an aldehyde (compound (2a)) via a dicyanoethylene compound (compound (2b)) and a 2-mercaptopyrimidine compound (compound (2c)) or a 2-mercaptodihydropyrimidine compound (compound (2d)).

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

In addition, compound (2d) includes an isomer that has a double bond differently located in the ring.

Each reaction shown in Scheme 1 can be carried out according to the methods described in each reference.

More specifically, the following method may enable this.

First, compound (2a) and malononitrile compound (11) can be reacted according to the method of reference (see, For example, WS Emerson, TM Patrick, J. Org. Chem., 790, 14, 1949). Namely, compound (2a) can be reacted with an equimolar amount to a molecular excess of malononitrile (11) without solvent or in an inert solvent such as water, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), diethyl ether, tetrahydrofuran (THF), dioxane , acetone, methyl ethyl ketone (MEK), methanol, ethanol, methylene chloride, dichloroethane, and chloroform to give compound (2b). Preferably, the above reaction is carried out in an inert solvent, especially ethanol. Although the above reaction can be carried out without any catalyst, it is preferable to use catalytic up to an equimolar amount of catalyst per mole of compound (2a). Examples of the catalyst include an organic base such as piperidine or a salt thereof, an amino acid such as glycine and an ammonium salt such as ammonium acetate. Among them, piperidine is a particularly preferred base. The temperature of the above reaction may be room temperature to elevated temperature, even if any solvent and catalyst are used or not used. Particularly, room temperature is preferred.

Then the compound (2b) from the above reaction can be converted to the compound (2c) or to the compound (2d) or to a mixture thereof by reaction with thiourea (12). This reaction can be carried out according to the method of reference (see, for example, Daboun, HA; El-Reedy, AM; Z. Naturforsch., 1983, 38 (12), 1686). The reaction mentioned above in detail can be carried out with an equimolar amount to the molecular excess of thiourea (12) per one mole of the compound (2b), without a solvent or in an inert solvent such as water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, and chloroform. Optionally some bases such as potassium carbonate, sodium hydroxide, sodium acetate, sodium, methoxide, sodium ethoxide and triethylamine may be added to the reaction medium. Preferably, the above reaction can be carried out in ethanol, in the presence of sodium ethoxide. The temperature conditions of the reaction in the above process may be room temperature to an elevated temperature, preferably the boiling point of the solvent.

Then, according to the method of Scheme 1, compound (2c) or compound (2d) or a mixture thereof obtained from the above reaction can be reacted with compound (13) (i.e. a substituted pyridyl lower alkyl compound with a leaving group arylsulfonyloxy group to form a compound of the invention (1) or a dihydro-compound (2e) or a mixture thereof. This reaction can be carried out using an equimolar amount to the molecular excess of compound (13) per one mole of compound (2c) or compound (2d) or a mixture thereof. The reaction can be carried out without a solvent or in an inert solvent such as halogen, alkylsulfonyloxy) such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, and chloroform. Some bases such as potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine can then be added to the reaction medium, if necessary. Among the above conditions, a reaction using DMF as the reaction solvent and in the presence of sodium bicarbonate as a base is particularly preferred. The reaction may be carried out at room temperature to an elevated temperature, preferably at room temperature.

Compound (13), which is used in the above reaction, is a new compound due to the type of group R² and groups R³. Such new relationships will be mentioned below.

Furthermore, the dihydro-compound (2e) of the invention obtained in the above reaction can be converted to the compound (1) of the invention in an oxidation reaction. This reaction can be carried out without a solvent or in an inert solvent such as water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, ethyl acetate, methylene chloride, dichloroethane, and chloroform using a catalytic amount to excess molecular oxidant per mole of dihydro compound (2e) such as DDQ (2,3-dichloro5,6-dicyano-p-benzoquinone) and NBS (N-bromosuccinimide). In this way, the compounds of the invention (1) can be prepared. Among the above-mentioned conditions, the reaction using ethanol as the reaction solvent and in the presence of NBS, or using dioxane as the reaction solvent and in the presence of DDQ is particularly preferred. The temperature conditions of the above reaction may be room temperature to an elevated temperature, preferably the boiling point of the solvent.

The compounds of the present invention may also be prepared according to the method of Scheme 2 below.

Diagram 2

<img file="PL1740574T3_D0054.tif" />

<img file="PL1740574T3_D0055.tif" />

NHR¹ NHR¹

<img file="PL1740574T3_D0056.tif" />

<img file="PL1740574T3_D0057.tif" />

in which R¹, R², R³ and X are defined the same as in Scheme 1 above, provided that R¹ does not mean a hydrogen atom.

According to the method of Scheme 2, compound (1) according to the invention can be produced by reacting between compound (3a), which is produced by reacting thiourea (12) with compound (13), and compound (2b), via compound (2e ). Accordingly, compound (1) of the invention can be obtained as a mixture with compound (2e) via compound (2e) (dihydropyrimidine compound) by the above reaction.

The compound (13) used herein as the starting compound includes both a known compound and a new compound as listed in Scheme 1. Such new compounds will be listed below.

In addition, compound (2b) can be produced by reacting between compound (2a) and compound (11) shown in Scheme 1 above.

Compound (2e) includes an isomer that has a double bond differently located in the ring.

In the method shown in Scheme 2, first an equimolar amount to the molecular excess of compound (13) is reacted with one mole of thiourea (12) without solvent or in an inert solvent such as water, DMF, DMSO, diethyl ether, THF, dioxane, acetone , MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform. This reaction can be carried out according to the synthetic method

S-alkyl isothioureas as described in the reference such as Urquhart, GG; Gates, JW Jr; Connor, R .; Org. Synth., 1941, 21, 36. Some bases such as potassium carbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide and triethylamine, or some mineral acids such as hydrochloric acid and sulfuric acid, or some organic acids such as acetic acid. Preferably the reaction solvent is ethanol. The reaction may be carried out at room temperature to an elevated temperature, preferably at an elevated temperature (especially about 60 ° C). In this way, compound (3a) can be obtained as the free compound or as a salt.

Then, to the obtained compound (3a) (can be in the form of a free compound or in the form of a salt), an equimolar amount is added to the molecular excess of the compound (2b) without a solvent or in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform, an equimolar amount of the excess molecular base is optionally added to the reaction mixture to carry out the reaction, such as potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine, and diisopropylethylamine. This reaction can be carried out according to the method of reference (ElSharabsy, SA; Abdel Gawad, SM; Hussain, SM; J. Prakt. Chem., 1989, 331 (2), 207). In this reaction, for example, ethanol can be represented as the preferred solvent. In addition, it is also preferred to add sodium bicarbonate to the reaction medium. The reaction may be carried out at room temperature to an elevated temperature, preferably to the boiling point of the solvent. In this way, a compound (1) according to the invention or a dihydro-compound (2e) or a mixture thereof can be obtained. The dihydro-compound (2e) of the invention obtained as above can be converted to the compounds (1) of the invention by the oxidation reaction shown in Scheme 1 above.

In the production process according to Scheme 2, the compound (3a) is prepared from thiourea (12), the above compound is isolated and then this compound is reacted with the compound (2b). However, without separating the compound (3a), the reaction in which the compound (2b) is added to the reaction mixture under the same conditions can also be carried out to the compound (1) according to the invention or the dihydro-compound (2e) or a mixture thereof.

The compound of the present invention can also be prepared according to the method of Scheme 3 below.

Diagram 3

NH2

AND

H2NS (12)

<img file="PL1740574T3_D0058.tif" />

NHR¹

NHR¹

<img file="PL1740574T3_D0059.tif" />

ABOUT)

<img file="PL1740574T3_D0060.tif" />

in which R¹, R², R³ and X are defined the same as in Scheme 1 above, provided that R¹ does not mean a hydrogen atom.

According to the method of Scheme 3, with or without separation of the compound (3a) thiourea (12) obtained by reaction between the compound (1) according to or a mixture thereof and a compound (13), the invention or its dihydro-compound (2e reacting compound (3a) simultaneously with compound (2a) and malononitrile (11).

The reaction for producing compound (3a) is shown in Scheme 2 above. The reaction of the compound (3a) with the compound (2a) and malononitrile (11) can be carried out as follows: the compound (3a) (can be in the form of a free compound or in the form of a salt) is reacted with an equimolar amount to a molecular excess of the compound (2a) and equimolar an amount to a molecular excess of malononitrile (11) under the same reaction conditions as in the above Scheme 2 for the preparation of the compound (1) according to the invention or its dihydro-compound (2e) or a mixture thereof.

The dihydro-compound (2e) of the invention obtained as above can be converted to the compound (1) of the invention by oxidation reaction according to the above Scheme 1.

In addition, the compounds of the invention can be prepared according to known methods from compounds obtained by the above various methods as a starting compound as mentioned below.

Preparation of starting compound

Compound (13), which is used as a starting substance in Schemes 1 to 3 above, is a new compound due to its type of group R² and groups R³. For example, such compounds can be prepared according to the method of Schemes 4-9 below.

Diagram 4

X1

-ν

4a)

CH 2 X²^H R10 _NR _R9

15)

X1

R10

2 N ²R9

4b) where X¹ and X² means leaving groups such as halogen, arylsulfonyloxy, alkylsulfonyloxy. In addition, -NR⁹R¹⁰ means a group

-N \ —Z¹ \ /

N Z2 or (in each group Z¹, FROM² and R⁵ are defined the same as in the above general formula (1)).

According to the method of Scheme 4, the starting material (compound (4b) according to the invention, which R² is a methylene group, R³ means group (3), group (6) or group (8), can be produced by reaction between the known compound (4a) and the compound (15).

In the reaction, the compound (15) is generally used in an equimolar amount to the molecular excess per one mole of the compound (4a). The reaction can be carried out without a solvent or in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane, and chloroform. Optionally, the reaction medium may contain an equimolar amount to an excess of molecular base per one mole of compound (4a), such as potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine and diisopropylethylamine. In this way, compound (4b) can be obtained. This reaction using ethanol as the solvent and using a molecular excess of compound (15) per one mole of compound (4a) and without a base is preferred. The reaction temperature may be room temperature to elevated temperature, preferably room temperature.

Diagram 5

ABOUT

<img file="PL1740574T3_D0061.tif" />

(16)

5a)

5b)

ABOUT ^ABOUT

R12 O

<img file="PL1740574T3_D0062.tif" />

5c)

WELL

R11

HO

<img file="PL1740574T3_D0063.tif" />

(5d)

WELL

-R11

X

<img file="PL1740574T3_D0064.tif" />

(5e)

WELL

R11 where R¹¹ means groups, OR⁵ or

Z1 (in each group, R⁵ and Z¹ are defined the same as the general formula (1)), R¹² is a lower alkyl group, an aryl group or a halogen-lower alkyl group, and X is defined as in Scheme 1 above.

According to Scheme 5, a starting material (compound (5e)) according to the invention can be prepared in which R²is a methylene group, R³ means group (4), group (5) or group (7). Any reaction illustrated by this method can be carried out as follows. Compound (5a) obtained according to a conventional method from 6-methyl-2-picolinic acid (16) (or 6-methyl-3-picolinic, 6-methyl-4-picolinic, 6-methyl-5-picolinic acid) can be reacted with equimolar an amount of excess molecular weight of an oxidizing agent such as chloroperbenzoic acid (m-CPBA) and hydrogen peroxide in an inert solvent such as diethyl ether, THF, dioxane, acetonitrile, methylene chloride, dichloroethane and chloroform to give compound (5b). The reaction temperature may be ice temperature to solvent reflux temperature. Particularly preferred is a reaction in which an excess amount of an oxidizing agent such as m-CPBA is used in chloroform at room temperature.

Then, to the obtained compound (5b), an equimolar amount can be added to the excess molecular weight of the organic anhydride, such as acetic anhydride, without a solvent or in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform and the mixture can be reacted at room temperature or with heating to give compound (5c).

In addition, the obtained compound (5c) is subjected to hydrolysis in an inert solvent such as water, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform in the presence of an equimolar amount to a molecular excess of base, such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, sodium acetate, sodium methoxide and sodium ethoxide at room temperature or with heating to give compound (5d). The reaction carried out in methanol with an excess of potassium hydroxide and with heating to reflux is particularly preferred. In addition, the compound (5d) obtained in this reaction can also be obtained directly in one step from the compound (5b). In such a reaction, compound (5b) can be reacted with an equimolar amount to a molecular excess of trifluoroacetic anhydride in an inert solvent such as diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform, or without solvent. and then hydrolyze with water, methanol, ethanol, etc. Preferably this reaction is carried out with an excess amount of trifluoroacetic anhydride without solvent, then methanol is added and the mixture is stirred.

In conclusion, the reaction from compound (5d) to compound (5e) can be carried out by the following three methods.

Method 1): Compound (5d) is reacted with an equimolar amount to excess molecular halogenating agent such as thionyl chloride, thionyl bromide and oxalyl chloride, without a solvent or in an inert solvent such as diethyl ether, THF, dioxane, acetone, MEK, acetonitrile , methylene chloride, dichloroethane and chloroform.

Method 2): Compound (5d) is reacted with an equimolar amount of excess molecular weight of an alkylsulfonyl chloride such as methanesulfonyl chloride without a solvent or in an inert solvent such as diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform in the presence of an equimolar amount to excess molecular base, such as potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine and diisopropylethylamine.

Method 3): Compound (5d) is reacted with an equimolar amount to a molecular excess of haloalkyl such as carbon tetrachloride, chloroform and carbon tetrabromide in the presence of an equimolar amount to excess molecular phosphine ligand such as triphenylphosphine and tri (n-butyl) phosphine in inert solvent such as diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform.

Diagram 6

R14

Si R14

R13 O

<img file="PL1740574T3_D0065.tif" />

17)

R14

R12 O

<img file="PL1740574T3_D0066.tif" />

6b)

R14

Si R14

R14

H R9 N.

<img file="PL1740574T3_D0067.tif" />

R9

R10

N where R¹³ is a hydrogen atom or a protective group, R¹⁴ is a lower alkyl group. X is determined in the same way as in Scheme 1 above. R^{g * * * 9} and R¹⁰ are defined the same as in Scheme 4 above.

The protective group mentioned above, which is indicated as R¹³, includes typical protecting groups for an alcoholic hydroxy group such as acetyl, methoxymethyl and tetrahydropyranyl.

According to Scheme 6, compound (6e) can be produced, which is the starting material according to the invention, in which _R4 is an ethylene group, R³ means any of group (3), group (6) and group (8). Any reaction shown in this method can be carried out as follows. First, the compound (6a) with or without a protecting group on the hydroxyl group is coupled with an equimolar amount to a molecular excess of trialkyl silylacetylene (17) in a basically such as triethylamine, in the presence of a catalytic amount of an organic metal catalyst such as bis (triphenylphosphine) palladium chloride ( II) and an activator such as copper (I) iodide. This reaction can lead to compound (6b).

Then, compound (6b) can be desilylated in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform in the presence of an equimolar amount to excess molecular base such as potassium carbonate and sodium hydroxide to give compound (6c). In some cases, the protective group cannot be split off due to the difference in the protective group R¹². In this case, the protective group may be cleaved in any conventional manner. In addition, an equimolar amount of the excess compound (15) without solvent or in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, chloride is added to the obtained compound (6c). methylene, dichloroethane and chloroform, and the mixture can be reacted at ice to the boiling point of the solvent, optionally in the presence of an equimolar amount to a molecular excess of a base such as potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine and diisopropylethylamine of compound (6d). Boiling with a molecular excess of compound (15) in ethanol is preferred.

Finally, compound (6d) can be reacted by the same method of synthesizing compound (5e) as in Scheme 5 above to give the desired compound (6e).

for receiving to temperature

Diagram 7

ABOUT

CR15

HO '(7a) (19

HO

7b)

br

ABOUT

CR15

HO

7c)

ABOUT

CR15

ABOUT

CR15

ABOUT

CR15

7e)

7d) where R¹⁵ represents a lower alkoxy group. X is determined the same as in Scheme 1 above.

According to the method of Scheme 7, the starting material (compound (7d)) of the invention can be synthesized, wherein R² is a methylene group, R³ means group (9) and Z³is (c2) lower alkoxy; and starting material (compound (7e)} according to the invention wherein R² is a methylene group, R³ means group (10), Z³ is (c2) lower alkoxy.

In this method, detailed below, compound (7a) is first reacted with an equimolar amount to a molecular excess of lower alkylacrylate (19) to give compound (7b). This reaction can be carried out according to the following two methods.

Compound (7a) is reacted with compound (19) without a solvent or in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform, optionally in an inert gas atmosphere such as argon and nitrogen in the presence of an equimolar amount to a molecular excess of a base such as triethylamine and diisopropylethylamine, in the presence of a catalytic amount to an equimolar amount of an organic metal catalyst such as palladium (II) acetate and bis (triphenylphosphine) palladium chloride and in the presence of an equimolar amount to a molecular excess of a phosphine ligand such as triphenylphosphine and tri (o-tolyl) phosphine at room temperature or with heating (Heck reaction) (Method 1).

Compound (7a) is reacted with compound (19) without solvent or in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform. optionally in an atmosphere of inert gas such as argon and nitrogen, in the presence of an equimolar amount to excess molecular base, such as potassium carbonate, sodium bicarbonate, sodium hydroxide, sodium acetate, sodium methoxide, sodium ethoxide, triethylamine and diisopropylethylamine, in the presence of an equimolar amount to excess molecular phase transfer catalyst such as tetra (n-butyl) ammonium chloride and tetramethyl ammonium chloride, in the presence of a catalytic amount to an equimolar amount of an organic metal catalyst such as palladium (II) acetate and bis (triphenylphosphine) palladium chloride and optionally in the presence of an additional dehydrating agent such as molecular sieves and at room temperature or with heating (Heck reaction, Jeffer's conditions) (Method 2).

Among them, Method 2 is preferred, especially reaction under argon in DMF in the presence of an equimolar amount of tetra (n-butyl) ammonium chloride, a molecular excess of sodium bicarbonate, a molecular excess of molecular sieves (e.g., "3A 1/16", see Showa Kagaku Chemical Database) and catalytic amount of palladium (II) acetate at 80 ° C.

The resulting compound (7b) can then be reacted with hydrogen gas at atmospheric or elevated pressure in an inert solvent such as DMF, DMSO and diethyl ether, THF, dioxane, methanol, ethanol, acetonitrile and methylene chloride at room temperature or with heating at the presence of a catalytic amount of a hydrogenation catalyst such as platinum dioxide and palladium carbon to give compound (7c). Among these reactions, the reaction with vigorous stirring by means of hydrogen gas at atmospheric or elevated pressure (1-3 kgf / cm is particularly preferred)²) in methanol or ethanol at room temperature in the presence of a catalytic amount of platinum dioxide.

Compound (7c) obtained above can be converted to the desired compound (7d) by the same method in which compound (5e) is obtained from compound (5d) in Scheme 5 above.

In addition, the above compound (7b) can be reacted in the same manner as compound (5e) is obtained from compound (5d) in Scheme 5 above to provide compound (7e).

Starting material of a compound of the invention in which R²is a lower alkylene group and R³ is a group (9), group (10) or group (12), can be synthesized using the appropriate starting material in the method of Scheme 7.

Diagram 8

HO (8a)

CHO

ABOUT

Ph 3 P

<img file="PL1740574T3_D0068.tif" />

(8b)

R15

HO

N (7b)

ABOUT

<img file="PL1740574T3_D0069.tif" />

R15 where R¹⁵ is defined the same as in the above Scheme

7. Ph is a phenyl group.

As shown in Scheme 8 above, compound (7b) indicated in Scheme 7 above can also be prepared using known compounds (8a) as starting material according to Wittig reaction (A. Maercher, OR, 14, 270 (1965) BE Maryanoff et al., CRV, 89, 863 (1989)) or Wittig-Horner reaction (reaction using phosphonic acid ester instead of phosphonium salt in Wittig reaction).

In the case of a Wittig reaction, the desired compound (7b) can be obtained when compound (8a) is reacted with an equimolar amount to a molecular excess of compound (8b) without a solvent or in an inert solvent such as DMF, diethyl ether, THF, dioxane, methanol , ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform, optionally in an inert atmosphere such as argon and nitrogen, at ice temperature, room temperature or with heating. Reaction with a molecular excess of compound (8b) in DMF is particularly preferred.

The Wittig-Horner reaction can be carried out in the same manner, using the appropriate phosphonate ester of compound (8b) instead of compound (8b) and a suitable base such as sodium methoxide.

Starting material of compounds of the invention in which

R² is a lower alkylene group and R³ means group (9), group (10) or group (12), can be synthesized when the appropriate starting material is used in the method of Scheme 8.

Diagram 9

<img file="PL1740574T3_D0070.tif" />

R16

<img file="PL1740574T3_D0071.tif" />

= -R¹⁶

20) HO

N

<img file="PL1740574T3_D0072.tif" />

9a)

HO

N

<img file="PL1740574T3_D0073.tif" />

R16

9b) where R¹⁶ is a hydrogen atom or a group

ABOUT

<img file="PL1740574T3_D0074.tif" />

R17 whose R¹⁷ is a lower alkyl group.

According to the method of Scheme 9, a starting material (compound (9b)) of a compound of the invention in which R² is a methylene group and R³ is (2) a lower alkyl group; starting material (compound (9a)) of a compound of the invention in which R² is a methylene group and

R³ means group (9) provided that Z³ is lower alkoxy (c2); and starting material (compound (9c)) of a compound of the invention in which R² is a methylene group and R³means group (11) provided that Z³ is a group (c5) having a lower alkyl group at position 4.

In this method, the compound (1a) is first coupled with an equimolar amount to the molecular excess of the alkyne derivative (20) to give compound (9a). This reaction can be carried out in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform in the presence of an equimolar amount to a molecular excess such as triethylamine. diisopropylethylamine and t-butyl64 amine, in the presence of a catalytic amount of an organic metal catalyst such as tetrakis (triphenylphosphine) palladium (0) and palladium (II) chloride and in the presence of an activator such as copper (I) iodide, optionally in an inert gas such as argon and nitrogen, in the presence of an antioxidant such like BHT (butylhydroxytoluene). Particularly preferred is the reaction under argon in DMF in the presence of a molecular excess of t-butylamine, a catalytic amount of tetrakis (triphenylphosphine) palladium (0), copper (I) iodide and BHT at 80 ° C.

Then, the obtained compound (9a) can be reacted in the same manner as compound (7b) is converted to compound (7c) as in the above Scheme 7 for the preparation of compound (9b).

Compound (9b) is reacted in the same manner as compound (5d) is converted to compound (5e) as shown in Scheme 5 above to give the desired compound (9c).

Certain compounds of the invention can also be prepared according to various known synthetic methods from other compounds of the invention, obtained as starting material, by the above-mentioned methods, based on properties resulting from the basic structure and the type of substituent. The following methods for preparing compounds of the invention in which the present compound of the invention can be converted to another compound of the invention will be illustrated by the following schemes

Diagram 10

NHR 1

<img file="PL1740574T3_D0075.tif" />

<img file="PL1740574T3_D0076.tif" />

*&gt;

NHR1b

<img file="PL1740574T3_D0077.tif" />

in which R² and R³ are defined the same as in the above general formula (1). R^1a is lower alkylcarbonyl. R^1b5 is lower alkylcarbonyl than lower alkenylcarbonyl or phenylcarbonyl.

As shown in Scheme 10, a compound of the invention (compound 1B), wherein R¹ is hydrogen in the general formula (1) can be obtained by reacting the compound (1A) of the invention in which R¹ is an alkylcarbonyl group such as acetyl, with an equimolar amount to excess molecular base such as potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide, or an acid such as hydrochloric acid, sulfuric acid, acetic acid and citric acid, in an inert solvent such as water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform, and hydrolyzed. The hydrolysis reaction can be carried out at room temperature to an elevated temperature. In particular, preferably the hydrolysis reaction is carried out by mixing in a mixture of ethanol and water with an aqueous solution of hydrochloric acid at a temperature of 80 ° C.

Compound (1C) according to the invention wherein R¹ is lower alkylcarbonyl, lower alkenylcarbonyl and phenylcarbonyl, can be synthesized by reacting compound (1B) according to the invention in which R¹ is a hydrogen atom with an equimolar amount of excess molecular acylating agent such as acid chloride and active ester in an inert solvent such as DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform in the presence of an equimolar amount to excess molecular base, such as potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine, at ice temperature, room temperature or at elevated temperature.

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

Diagram 11

NHR¹

N

<img file="PL1740574T3_D0078.tif" />

1D) ^ -R⁴—N \ h (1E)

Z1a ^ r4_ / \ —Z1b (1F) in which R¹, R² and R⁴ are defined in the same way as for the above general formula (1). FROM^1a is (a12) lower alkylcarbonyl or (a28) lower alkoxycarbonyl. Group Z^1ais defined the same as group Z¹ in the general formula (1), with the exception of hydrogen, i.e., it means any of the groups selected from (a1) - (a31) and (a33) - (a38) in the general formula (1).

As shown in Scheme 11, a compound (1E) according to the invention, in which R³ means group (6) and Z¹ is (a32) a hydrogen atom in the general formula (1), can be synthesized by cleaving the leaving group with a compound (1D) according to the invention, wherein R³ means group (6) and Z¹ is a group (a12) or (a28), i.e., from a compound having a group that can be cleaved. More specifically, compound (1E) can be obtained when compound (1D) according to the invention is reacted with an equimolar amount to an excess molecular base such as potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide, and sodium ethoxide, or a mineral acid such as hydrochloric acid and sulfuric acid, or an organic acid such as acetic acid, trifluoroacetic acid and citric acid, in an inert solvent such as water, DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform or without solvent, and hydrolyzed. The hydrolysis reaction can be carried out at ice temperature, at room temperature or at elevated temperature. In particular, preferably a compound of the invention in which Z^1a BOC (t-butoxycarbonyl) is mixed with an excess of trifluoroacetic acid at room temperature without solvent.

As shown in Scheme 11, a compound (1F) according to the invention wherein R³ means group (6) and Z¹ is any of the groups selected from (a1) - (a31) and (a33) - (a38) in the general formula (1), can be synthesized from compound (1E) according to the invention in which R³ means group (6) and Z¹ is (a32) a hydrogen atom in the general formula according to the type of group Z¹ as below.

Compound (1E) can be reacted with an equimolar amount of excess molecular acylating agent such as alkylcarbonyl chloride, arylcarbonyl chloride and active ester in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, chloride methylene, dichloroethane and chloroform in the presence of an equimolar amount to a molecular excess of a base such as potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine at ice temperature, room temperature or at elevated temperature to provide a compound of the invention in which Z¹ is a substituted carbonyl group (a12) - (a28) or (a36) - (a38). It is preferred to react with a molecular excess of substituted carbonyl chloride in acetonitrile in the presence of triethylamine.

Compound (1E) can be reacted with an equimolar amount to an excess molecular weight of the carboxylic acid having various substituents, in an inert solvent such as DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform in the presence of an equimolar amount to an excess of molecular condensing agent such as DCC, WSC, BOP and DEPC, optionally in the presence of an equimolar amount to an excess of molecular activating agent such as HOSu, HOBt and HOOBt to obtain a compound of the invention in which Z¹ is substituted with a carbonyl group (a12) - (a28) or (a36) - (a38). The reaction can be carried out at any temperature conditions, ice temperature, room temperature and elevated temperature. In particular, the reaction is preferably carried out in the presence of WSC and HOBt at room temperature.

Compound (1E) can be reacted with an equimolar amount to a molecular excess of a sulfonylating agent such as alkylsulfonyl chloride and arylsulfonyl chloride in the presence of an equimolar amount to a molecular excess of a base such as potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine, in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform to give a compound of the invention in which Z¹ means any of the groups selected from (a29) (a31). The reaction can be carried out at any temperature condition of ice temperature, room temperature and elevated temperature. Preferably, the reaction is carried out in the presence of a molecular excess of diisopropylethylamine, at DMF at room temperature.

Compound (1E) can be reacted with an equimolar amount of excess molecular amount of an alkylating agent including an alkenylating agent such as an alkyl halide (for example, alkyl chloride) and alkylmethanesulfonate, in the presence of an equimolar amount of excess molecular base such as potassium carbonate, bicarbonate sodium, sodium acetate, sodium hydroxide, potassium hydroxide, triethylamine and diisopropylethylamine, in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform to give a compound of the invention in which Z¹ means any of the groups selected from (a1) - (a11) and (a33) - (a35). The reaction can be carried out at any temperature condition of ice temperature, room temperature and elevated temperature. In particular, the reaction is carried out with a molecular excess of an alkylating agent, preferably an alkyl halide, in the presence of a molecular excess of potassium carbonate in DMF at room temperature.

Compound (1E) can be reacted with an equimolar amount to the excess molecular weight of the aldehyde compound having a suitable substituent, in an inert solvent such as DMF, DMSO, diethyl ether, THF, dioxane, acetonitrile, methylene chloride, dichloroethane, chloroform, methanol and ethanol, optionally in the presence of a catalytic amount to excess molecular catalyst such as acetic acid to give an isolated or uninsulated imino compound. The imine compound may be reacted with an equimolar amount to excess molecular reduction agent per one mole of the compound (1E), such as sodium borohydride, sodium cyanoborohydride and diborane to provide a compound of the invention in which Z¹ is any of the groups selected from (a1) - (a11) and (a33) - (a35) (reductive alkylation). The reaction can be carried out under any temperature conditions of ice temperature, room temperature and elevated temperature. The preferred compound (1E) is reacted with a molecular excess of an aldehyde compound in the presence of 5 times acetic acid and an excess of sodium cyanoborohydride in DMF at room temperature.

A compound of the invention in which R³ means group (7) and Z¹ is (a32) a hydrogen atom in the general formula (1) and a compound of the invention in which R³ means group (8) and Z² is (b1) a hydrogen atom in the general formula (1), it can also be synthesized from a compound of the invention in which R³means group (7) and Z¹ is any group of (a12) and (a28) in the general formula (1) and from a compound of the invention in which R³ means group (8) and Z² means group (b2) in the general formula (1) as starting material as in a similar reaction for the preparation of compound (1E) from compound (1D) as shown in Scheme 11 above.

In addition, a compound of the invention wherein R³ means group (7) and Z¹ means any group of (a1) - (a31) or (a33) (a38) in the general formula (1) and a compound of the invention in which R³ means group (8) and Z² is any group from (b2) - (b8) in the general formula (1), can be prepared from a compound of the invention in which R³ means group (7) and Z¹ is (a32) a hydrogen atom in the general formula (1) and a compound of the invention in which R³ means group (8) and Z² is (b1) a hydrogen atom in the general formula (1) as a starting material as in a similar reaction for producing compound (1F) from compound (1E) as shown in Scheme 11 above.

Diagram 12

N

<img file="PL1740574T3_D0079.tif" />

1G)

NO ^ Lr4 J__FROM3a

NO ^ R ^ OOH, NO

-) - C-R4-Z3b

1H)

1I in which R¹, R² and R⁴ is defined the same as in the above general formula (1). FROM^3a is (c2) lower alkoxy. FROM^3b means group Z³ of general formula (1) except for the hydroxyl group and lower alkoxy group, i.e., any of the groups (c3) - (c22) in the general formula (1).

As shown in Scheme 12, a compound of the invention (1H), wherein R³ means group (9) and Z³ is (c1) a hydroxyl group can be synthesized from a compound (1G) of the invention in which R³ means group (9) and Z³ represents a lower alkoxy group. This reaction can be carried out, for example, by reacting the compound (1G) according to the invention with an equimolar amount to an excess molecular base such as potassium carbonate, sodium bicarbonate, sodium acetate, sodium hydroxide, potassium hydroxide, sodium methoxide and sodium ethoxide, acid mineral such as hydrochloric acid and sulfuric acid or organic acid such as acetic acid, trifluoroacetic acid and citric acid in an inert solvent such as water, DMF, DMSO, diethyl ether

THF, dioxane, acetone, MEK, methanol, ethanol, acetonitrile, methylene chloride, dichloroethane and chloroform or without solvent, and hydrolysis. The hydrolysis reaction can be carried out at ice temperature, room temperature or at elevated temperature. In particular, preferably a compound of the invention wherein Z^3a means tert-butoxy is mixed with an excess of trifluoroacetic acid at room temperature without solvent.

In addition, as shown in Scheme 12, a compound (II) according to the invention wherein R³ means group (9) and Z³ is a group selected from (c3) - (c22) in the general formula (1) can be synthesized from compound (1H) of the invention in which R³ means group (9) and Z³ is (c1) hydroxyl. More specifically, this method can be carried out by reacting compound (1H) of the invention with an equimolar amount to an excess molecular weight of the amine or aliphatic nitrogen containing heterocyclic compound with a suitable substituent corresponding to the desired Z³ in an inert solvent such as DMF, DMSO, THF diethyl ether, dioxane, acetone, MEK, acetonitrile, methylene chloride, dichloroethane and chloroform in the presence of an equimolar amount to excess molecular condensation such as DCC, WSC, BOP and DEPC, optionally in the presence of equimolar amounts to excess molecular activating agent such as HOSu, HOBt, HOOBt. In this way, compound (II) according to the invention can be obtained in which Z³ is a group selected from (c3) - (c20). The reaction can be carried out at any temperature conditions, ice temperature, room temperature and elevated temperature. In particular, the reaction is preferably carried out in DMF or acetonitrile in the presence of BOP or WSC and HOBt at room temperature.

A compound of the invention in which R³ means group (10) and Z³ is (c1) a hydroxyl group in the general formula (1) and a compound of the invention in which R³ means group (11) and Z³ is (c1) a hydroxyl group in the general formula (1), it can also be synthesized from a compound of the invention in which R³ means group (12) and Z³ is (c2) a lower alkoxy group in the general formula (1) and a compound of the invention in which R³ means group (11) and Z³ is (c2) a lower alkoxy group in the general formula (1) as the starting material as in a similar reaction for producing compound (1H) from compound (1G) as shown in Scheme above

12.

In addition, a compound of the invention, group (10) and Z³ means any group of formula (1) and a compound of the invention in which R³ is (c3) - (c22) in the general one in which R³ means group (11) and Z³ is any of the groups (c3) - (c22) in the general formula (1) can be prepared from a compound of the invention in which R³ means group (10) and Z³ is (c1) a hydroxyl group in the general formula (1) and a compound of the invention in which R³ means group (11) and Z³ is (c1) a hydroxyl group in the general formula (1) as a starting material as in a similar reaction for producing compound (II) from compound (1H) as shown in Scheme 12 above.

The desired compounds obtained from each of the processes shown in the scheme above and compounds of the invention may be isolated or purified in the form of the free compound or in the form of their salts according to a conventional method. Means for such isolation and purification include some typical chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various types of chromatography.

When the compound of the invention is a mixture of isomers as mentioned above, each isomer can be separated by a conventional method using a variety of physical properties between isomers. More specifically, the isolation of the stereochemically pure isomer from racemic compounds can be carried out by means of a typical racemic resolution in which the racemic compounds are formed in the form of diastereomeric salts with a usual optically active acid such as tartaric acid and then separated. The isolation of each isomer from the diastereomeric mixture can be carried out, for example, by means of fractionated crystallization and chromatography. In addition, the optically active compounds of the invention can also be prepared when an optically active starting compound is used.

Pharmaceutical composition according to the invention

The compounds of the invention and their salts have agonist activity at the A2a adenosine receptor, so they are useful as an adenosine A2a receptor agonist for mammals including human beings. Accordingly, the present inventions also provide pharmaceutical compositions as a drug such as an A2 adenosine receptor agonist.

The present pharmaceutical composition can be prepared into a conventional pharmaceutical formulation containing an effective amount of one or more compounds selected from the group consisting of compounds of the invention and their salts, and certain pharmaceutically acceptable carriers. Pharmaceutically acceptable carriers used in the pharmaceutical composition of the invention may be solid, such as an excipient, or liquid, such as a diluent. Examples of carriers include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol etc.

In addition, the pharmaceutical composition may be prepared in unit dosage formulation suitable for and a liquid formulation such as a tablet and liquid as well as administration. Examples include a solid suitable for oral administration, pill, capsule, granule, powder formulation for parenteral administration such as injection (intravenous injection, intramuscular injection etc.), eye drops, ophthalmic ointment, suppository, transdermal absorption agent, etc. In particular, a preferred pharmaceutical formulation is eye drops because it is believed that the pharmaceutical composition of the invention can be used as an intraocular pressure reducing agent, drug for the treatment of glaucoma, etc., based on the agonist activity of the A2a adenosine receptor.

Eye drops can be prepared according to a conventional method, for example by optionally adding an isotonic agent such as sodium chloride, glycerin to the compound of the invention (including its salt, as defined below); a stabilizer such as sodium edetate; an antiseptic such as benzalkonium chloride and parabens; pH adjusters such as sodium dihydrogen phosphate, dihydrogen sodium phosphate, boric acid, sodium tetraborate (borax), hydrochloric acid and sodium hydroxide.

The solid drug of the present invention for oral administration, such as a tablet, powder and granules, can be prepared by mixing the compound of the invention with at least one inert carrier such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, meta acid silicon and magnesium aluminate and the formation of the mixture according to a conventional method. Additional suitable additives may then be included in the formulation, for example a lubricant such as magnesium stearate; disintegrator such as croscarmellose calcium; a stabilizer such as lactose; a solubilizing agent such as glutamic acid and aspartic acid; etc. Then, a sweetener, flavoring agent, flavoring agent, antiseptic etc. can be incorporated. The tablet and pill may be coated with a sugar coating layer such as sucrose, gelatin, hydroxypropyl cellulose and hydroxypropyl methylcellulose phthalate or a layer of gastric or enteric coated material, if necessary.

A liquid drug for oral administration, such as an emulsion, solution, suspension, syrup and elixir, can be prepared by dissolving or dispersing the compound of the invention in a generally used inert diluent such as purified water and ethanol. Liquid medications may also contain an auxiliary agent such as wetting agent and suspending agent, sweetener, flavoring agent, flavoring agent, antiseptic, etc.

The injection for parenteral administration includes an aqueous aseptic or non-aqueous solution, suspension, emulsion, etc., and the aqueous solution and suspension may be prepared according to a conventional method, for example using distilled water for injection and brine as a diluent. The non-aqueous solution and suspension may be prepared according to a conventional method, for example using propylene glycol, polyethylene glycol or a vegetable oil such as olive oil; alcohols such as ethanol; a diluent or carrier such as polysorbate 80.

The solution or auxiliary, wetting, stabilizer suspension may then contain an antiseptic, dispersing agent such as an emulsifying agent, e.g. lactose) and a solubilizing agent (e.g. glutamic acid and aspartic acid). The injection is sterilized according to a conventional method, for example by filtration using a filter to remove bacteria, adding an antibacterial agent or using radiation such as gamma radiation. In addition, an injection may also be prepared as a formulation prepared immediately prior to use, by dissolving the aseptic solid injectable drug prepared prior to use in aseptic water or aseptic solvent.

The dosage regimen of the pharmaceutical composition of the present invention in each formulation will be determined in each case depending on the condition of the patients being administered the pharmaceutical composition (subject of administration), age, sex, etc. Generally, the dose of eye drops that contain the pharmaceutical composition of the present invention can be set as such that eye drops containing the active compound at a concentration of 0.0001-10% (w / v) are instilled or brushed once to several times a day. The amount of eye drops for single use is generally about 0.001-1 ml for an adult.

In the case of an oral drug or injection of a pharmaceutical composition of the invention, the dosage can be determined so that the compound of the invention is administered in an amount of 0.001-1000 mg per day for an adult. The daily dose can be administered once per day, but preferably it can be divided into several times. The above dosage is only a guide and can therefore also be increased or decreased. As mentioned above, it is preferred to determine the dosage each time to be used depending on different conditions. Accordingly, depending on the condition, the reduced dosage may still have adequate effects.

Industrial use

The compounds of the invention exhibit adenosine A2a receptor activating activity (i.e., adenosine A2a agonist receptor activity) and are useful for the prevention and / or treatment of glaucoma and intraocular hypertension, due to the intraocular pressure-lowering effect.

The best way to carry out the invention

The present invention presented below is illustrated by Reference Examples for the production of starting compounds and by an Example of the preparation of compounds of the invention, as well as by means of pharmacological experiments and tests, but should not be constructed to limit the above invention.

Nuclear magnetic resonance (NMR) spectra in the examples below were measured under the following conditions. The abbreviations are as follows.

Device: JNM-AL300 (JEOL)

Internal benchmark: TMS s: singlet, d: doublet, t: triplet, q: quartet, quint: quintet, sext: sextet

The following abbreviations have been used in the examples.

IPE: isopropyl ether

WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

LiAlH4: lithium aluminum hydride

THF: tetrahydrofuran

TBAF: tetrabutylammonium fluoride solution TBAF / THF: 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 reagent: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

TFA: trifluoroacetic acid

Reference Example Methyl 1- (4-formylphenyl) carbamate (560 mg) and malononitrile (206 mg) were dissolved in 10 mL of ethanol and one drop of piperidine was added to the resulting solution, followed by stirring at room temperature for 3 hours. IPE (10 mL) was added to the reaction mixture and the precipitated crystals were filtered off to obtain 441 mg of methyl [4- (2,2-dicyanovinyl) phenyl] carbamate as a yellow powder.

¹H-NMR (CDCl₃) δ: 7.90 (2H, d, J = 8.7 Hz), 7.65 (1H, s), 7.56 (2H, d, J = 8.7 Hz), 6.92 (1H, broad s), 3.83 (3H, s). Reference Example 2

To 20 ml of absolute ethanol, 250 mg of metallic sodium was added in small portions. After complete dissolution, 760 mg of thiourea was added to the above solution, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture, 2.11 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide was added, and the mixture was heated to reflux for 3 hours. Then the solvent was removed from the reaction mixture under reduced pressure, and the residue was dissolved in 30 ml of water. Then, the mixture was acidified by the addition of small portions of acetic acid, 30 ml of ethyl acetate were added, and the solution was stirred overnight. Filtration of the precipitated material gave 1.2 g of N- [4- (6-amino-5-cyano-2-mercapto-2,3-dihydropyrimidin-4-yl) phenyl] acetamide as a white powder.

¹H-NMR (DMSO-d₆) δ: 9.98 (1H, s), 9.65 (1H, broad 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

2,6-bis (bromomethyl) pyridine (265 mg) was suspended in 2 mL of ethanol, 87 mg of morpholine was added at ice temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (methylene chloride - ethanol - triethylamine = 400: 20: 1 (v / v, similarly below) to obtain 90 mg of 4- (6-bromomethylpyridin-2- ylmethyl) morpholine as a white powder.

¹H-NMR (CDCl₃) 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) 2.3 g of 6-bromopyridin-2-ylmethyl acetate, 1.18 g of trimethylsilylacetylene, 210 mg of bis (triphenylphosphine) palladium (II) chloride, 114 mg of copper (I) iodide and 12 ml were added to a round-bottomed flask. triethylamine, and then the mixture was heated to reflux under argon for 5 hours. After allowing to cool, the mixture was concentrated to dryness under reduced pressure, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, 7 mL of methanol and 30 mL of 1N aqueous potassium hydroxide solution were added to the residue, and the mixture was stirred for 1 hour. The reaction mixture was acidified with 1N hydrochloric acid and concentrated under reduced pressure. The concentrated solution was basified with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (hexane-ethyl acetate = 4: 1) to give 212 mg (6-ethynylpyridin-2-yl) methanol as a white powder.

¹H-NMR (CDCl₃) 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) (6-Ethynylpyridin-2-yl) methanol (320 mg) and morpholine (1 g) were dissolved in 3 ml of ethanol and the solution was heated to reflux under argon for 24 hours. After allowing the reaction mixture to cool, the ethanol will be removed under reduced pressure, and the residue basified with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent would be removed. The residue was purified by silica gel chromatography (chloroform - methanol - aqueous ammonia = 200: 10: 1) to obtain 122 mg of [6- (2-morpholin-4-ethylethyl) pyridin-2-yl] methanol as yellow oil.

<td></td><td>¹H-NMR</td><td>(CDCl₃) δ:</td><td>7.60 (1H, t, J = 7.8 Hz), 7.08 (1H,</td>

<td>d, J.</td><td> = 7,8</td><td>Hz), 7.03</td><td>(1H, d, J = 7.8 Hz), 4.72 (2H, s),</td>

<td> 3,73</td><td>(4H, vol</td><td>, J = 4.5</td><td>Hz), 3.00 (2H, dd, J = 10, 8.7 Hz),</td>

<td> 2,77</td><td colspan="2">(2H, dd, J = 10,</td><td>8.7 Hz), 2.53 (4H, t, J = 4.5 Hz).</td>

<td></td><td> (3)</td><td colspan="2">[6- (2-morpholin-4-ylethyl) pyridin-2-yl] methanol</td>

<td> (122</td><td>mg) and</td><td colspan="2">diisopropylethylamine (104 mg) was dissolved</td>

in 2.5 ml of dichloromethane and 47 μΐ of methanesulfonyl chloride are added dropwise to the solution at ice temperature, and then the mixture is stirred at room temperature overnight. After removing the solvent from the reaction mixture under reduced pressure, the residue was purified by silica gel chromatography (chloroform - methanol - aqueous ammonia = 300: 10: 1) to obtain 80 mg of 4- [2- (6-chloromethyl-pyridin-2-yl) ) ethyl] morpholine as a yellow oil.

¹H-NMR (CDCl₃) 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- (t-butyldimethylsilanyloxymethyl) pyridine-2-carboxaldehyde (4.29 g) was dissolved in 50 ml DMF and 7.14 g (carboxymethylene) triphenylphosphate was added to the solution, followed by stirring at room temperature for 1 hour . 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 concentrated to dryness under reduced pressure. To the residue, 100 ml of hexane-ethyl acetate (5: 1) was added, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 10: 1) to obtain

5.45 g of ethyl 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] acrylate in the form of a light yellow oil.

<td></td><td>¹H-NMR</td><td>(CDCl₃)</td><td>δ: 7.72 (</td><td>1H, t, J = 7.5 Hz</td><td> ), 7,66</td><td>(1H, d,</td>

<td>J</td><td>= 15.6 Hz</td><td> ), 7,49</td><td>(1H, d, J</td><td>= 7.5 Hz), 7.29 (</td><td>1H, d,</td><td>J = 7.5</td>

<td>h</td><td> ), 6,88 (</td><td>1H, d,</td><td>J = 15.6</td><td>Hz), 4.83 (2H,</td><td>s), 4,</td><td>27 (2H,</td>

<td>q,</td><td>J = 7.2</td><td>Hz), 1</td><td>, 33 (3H,</td><td>t, J = 7.2 Hz),</td><td> 0,97 (</td><td>9H, s),</td>

<td> 0,</td><td>13 (6H, p</td><td> ).</td><td></td><td></td><td></td><td></td>

<td></td><td> (2) 3-</td><td colspan="5">[6- {t-butyldimethylsilanyloxymethyl) pyridin-</td>

Ethyl 2-yl] acrylate (5.45 g) was dissolved in 100 mL of ethanol, and 200 mg of platinum dioxide was added to the solution, followed by stirring at atmospheric hydrogen pressure at room temperature for 5 hours. After flushing with nitrogen, the catalyst was filtered off and the solvent removed to give 5.07 g of ethyl 3 [6- (t-butyldimethylsilanyloxymethyl) -pyridin-2-yl] propionate as a pale yellow oil.

<td>(CDCl₃) δ:</td><td> 7,60</td><td>(1H, t,</td><td>J =</td><td> 7,</td><td> 5</td><td>Hz),</td><td> 7,33</td>

<td>= 7.5 Hz),</td><td> 7,03</td><td>(1H, d,</td><td>J =</td><td> 7,</td><td> 5</td><td>Hz),</td><td> 4,79</td>

<td>, 12 (2H, q,</td><td>J = 7,</td><td>2 Hz),</td><td> 3,07</td><td>(2H</td><td>^,</td><td>t, J.</td><td> = 7,5</td>

<td>(2H, t, J =</td><td>7.5 Hz)</td><td> , 1,23</td><td>(3H,</td><td>t</td><td>J</td><td> = 7,2</td><td>Hz),</td>

(2H, s),

Hz), 2.7

0.96 (9H, s), 0.11 (6H, s).

(3-) Ethyl 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] propionate (5.07 g) was dissolved in 100 ml of ethanol and 23.5 ml of a 1N aqueous sodium hydroxide solution was added to the solution, followed by stirring the mixture room temperature within 2 hours. The reaction mixture was concentrated to about half volume under reduced pressure, after the addition of ice water, the solution was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The residue was purified by silica gel chromatography (chloroform - methanol = 10: 1) to give 2.77 g of 3- [6- (t-butyldimethylsilanyloxymethyl) -pyridin-2-yl] -propionic form of a colorless powder.

<td></td><td>¹H-NMR (CDCl₃) δ:</td><td>7.77 (1H,</td><td>t, J =</td><td> 7,5</td><td>Hz),</td><td> 7,47</td>

<td>(1H,</td><td>d, J = 7.5 Hz),</td><td>7.13 (1H,</td><td>d, J =</td><td> 7,5</td><td>Hz),</td><td> 4,84</td>

<td>(2H,</td><td>s), 3.15 (2H, t,</td><td>J = 6.0 Hz)</td><td> , 2,82</td><td>(2H,</td><td>t, J.</td><td> = 6,0</td>

<td>Hz),</td><td colspan="2">0.96 (9H, s), 0.14 (6H, s).</td><td></td><td></td><td></td><td></td>

<td></td><td>(4) Acid 3- [6- (vol</td><td colspan="5">-butylodimetylosilanyloksymetylo) -</td>

pyridin-2-yl] -propionic (1.65 g) was dissolved in 20 ml of methylene chloride and 584 μΐ morpholine, 1.6 g of WSC and 1.56 ml of triethylamine were added to the solution, followed by stirring at room temperature overnight

The reaction mixture was diluted with chloroform, 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 chromatography (chloroform: methanol = 30: 1) to obtain 1.91 g of 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] -1-morpholin-4-propane-1-one in the form of yellow oil.

<td></td><td>¹H-NMR (CDCl₃) δ</td><td> : 7,60</td><td>(1H, t,</td><td>J</td><td> = 7,5</td><td>Hz),</td><td> 7,33</td>

<td>(1H,</td><td>d, J = 7.5 Hz)</td><td> , 7,08</td><td>(1H, d,</td><td>J</td><td> = 7,5</td><td>Hz),</td><td> 4,79</td>

<td>(2H,</td><td colspan="2">s), 3.62-3.43 (8H, m)</td><td colspan="2">, 3.11 (2H,</td><td>t, J =</td><td> 7,5</td><td>Hz),</td>

<td> 2,77</td><td>(2H, t, J = 7.5</td><td>Hz), 0,</td><td>96 (9H, p</td><td> ),</td><td>0.12 (6H,</td><td>s).</td><td></td>

<td></td><td>(5) For suspension</td><td>420 mg</td><td>LiAlH₄ in</td><td> 20</td><td>ml THF</td><td colspan="2">was added dropwise</td>

a solution of 1.9 g 3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] -1-morpholin-4-ylpropane-1-one in 30 ml THF at ice temperature. The reaction mixture was stirred at room temperature for 3 hours, excess LiAlH₄ quenched with water and the solution filtered through Hyflo Super-Cel (Nacalai Tesque) and separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the residue was purified by silica gel chromatography (methylene chloride - ethanol = 40: 1) to give 760 mg of 4- {3- [6- (t-butyl-dimethylsilanyloxy-methyl) ) pyridin-2-yl] propyl} morpholine.

Then to a solution of 760 mg 4- {3- [6- (t-butyldimethylsilanyloxymethyl) pyridin-2-yl] propyl} morpholine in 4 ml THF at ice temperature, 4.34 ml TBAF / THF solution (1 mol / l) was added dropwise. . The solution was stirred at room temperature for 2 hours, the solvent removed and the residue purified by silica gel chromatography (methylene chloride - ethanol = 40: 1) to obtain 495 mg of [6- (3-morpholin-4-ylpropyl) pyridin-2- yl] methanol.

In addition, to a solution of 495 mg of [6- (3-morpholin-4-propyl) pyridin-2-yl] methanol and 104 mg of diisopropylethylamine in 20 ml of methylene chloride at ice temperature, 0.18 ml of methanesulfonyl chloride was added dropwise and the mixture was stirred at room temperature during the night. After removal of the solvent, the residue was purified by silica gel chromatography (methylene chloride - ethanol = 40: 1) to obtain 290 mg of 4- [3- (6-chloromethylpyridin-2-yl) propyl] morpholine as a yellow powder.

¹H-NMR (CDCl₃) 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

2,6-bis (chloromethyl) pyridine (352 mg) was suspended in 4 ml of ethanol and 372 mg of N- (t-butoxycarbonyl) piperazine was added to the suspension at ice temperature, and then the suspension was stirred at room temperature overnight.

The reaction mixture was concentrated under reduced pressure, the residue was added to water and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent removed. The residue was purified by silica gel chromatography (methylene chloride - ethanol = 30: 1) to give 250 mg of 4- (6-chloromethylpyridin-2-ylmethyl) piperazine-1-carboxylate (t-butyl) as a colorless oil.

¹H-NMR (CDCl₃) 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 ( 4 H, t, J = 5.1 Hz), 1.48 (9H, s).

Reference Example 7 (1) 6-Methylpicolinic acid (1.37 g) and morpholine (870 mg) were dissolved in 30 ml DMF and 1.6 g HOBt was added with stirring at ice temperature. The mixture was stirred at the same temperature for 15 minutes, additionally 2.3 g of WSC was added and the solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate.

resulting mixture obtained. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent would be removed. The obtained residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine 900: 30: 1) to obtain 1.71 g (6-methylpyridin-2-yl) morpholin-4-ylmethanone as a colorless oil.

¹H-NMR (CDCl₃) 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, broad s), 3.67-3.58 (4H, m), 2.57 (3H, s).

(2) (6-methylpyridin-2-yl) morpholin-4-ylmethanone (1.38g) was dissolved in 10 ml chloroform to the solution and 1.77 g m-CPBA in 23 ml chloroform was added dropwise, and the mixture was stirred at room temperature for one day. 15 ml of a 10% aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The obtained residue was purified by silica gel chromatography (methylene chloride methanol - triethylamine = 1000: 25: 1} to give 1.26 g (6-methyl-1-oxypyridin-2-yl) morpholin-4-ylmethanone as a white powder.

¹H-NMR (CDCl₃) 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) To 1.26 g (6-methyl-1-oxypyridin-2-yl) morpholin-4-ylmethanone, 0.53 ml acetic anhydride was added and the mixture was stirred at 100 ° C for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine - 1000: 25: 1) to obtain

1.13 g 6- (morpholine-4-carbonyl) pyridin-2-ylmethyl acetate as a yellow oil.

¹H-NMR (CDCl₃) 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, broad s), 3.67-3.65 (4H, m), 2.17 (3H, s).

(4) To 1.13 g of 6- (morpholine-4-carbonyl) pyridin-2-methylacetate, 233 mg potassium hydroxide and 1.5 ml ethanol were added and the mixture was heated to reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and extraction was carried out with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (chloroform-methanol-triethylamine = 500: 25: 1) to give 530 mg (6-hydroxymethylpyridin-2-yl) morpholin-4-ylmethanone as a white powder.

¹H-NMR (CDCl₃) 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, wide s), 3.6.8 (2H , t, J = 4.8 Hz), 3.58 (2H, t, J = 4.8 Hz).

(5) To a solution of 530 mg (6-hydroxymethylpyridin-2-yl) morpholin-4-ylmethanone and 614 mg diisopropylethylamine in 10 ml of methylene chloride at ice temperature was added dropwise 0.28 ml of methanesulfonyl chloride and the mixture was stirred at room temperature overnight under reduced pressure

The reaction mixture was concentrated under and the residue was purified by silica gel chromatography (methylene chloride ethanol = 50: 1) to give 570 mg (6-chloromethylpyridin-2-yl) morpholin-4-ylmethanone as a yellow oil.

¹H-NMR (CDCl₃) 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, broad s), 3.69-3.65 (4H, m).

Reference Example 8 (1) t-butyl 6-methylpyridine-2-carboxylate (3.03 g) was dissolved in 30 ml of chloroform, and a solution of 3.96 g m-CPBA in 45 ml of chloroform was added dropwise to the above mixture, and the resulting mixture was stirred in room temperature overnight. The reaction mixture was transferred to a separatory funnel, 35 ml 10% aqueous Na was added₂SO₃ and the resulting mixture was separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (methylene chloride - ethanol = 30: 1) to give

3.28 g of t-butyl 6-methyl-1-oxypyridine-2-carboxylate as a colorless oil.

¹H-NMR (CDCl₃) δ: 7.29-7.13 (3H, m), 2.66 (3H, s), 1.63 (9H, s).

(2) To 3.28 g of t-butyl 6-methyl-1-oxypyridine-2-carboxylate, 1.5 mL of acetic anhydride was added, and the mixture was stirred at 100 ° C for 1 hour. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by silica gel chromatography (methylene chloride - ethanol = 30: 1) to give t-butyl 6-acetoxymethylpyridine-2-carboxylate as a yellow oil.

¹H-NMR (CDCl₃) 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 t-butyl 6-acetoxymethylpyridine-2-carboxylate was 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. The methanol was removed under reduced pressure, and then the residue was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed.

The residue was purified by silica gel chromatography (chloroform - ethanol - 50: 1) to give t-butyl 6-hydroxymethylpyridine-2-carboxylate as a yellow powder.

¹H-NMR (CDCl₃) 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) t-butyl 6-hydroxymethylpyridine-2-carboxylate (1.34 g) and diisopropylethylamine (1.24 g} was dissolved in 30 mL of methylene chloride, 0.54 mL of methanesulfonyl chloride was added dropwise at ice temperature, and the mixture was stirred at room temperature The reaction solvent was removed from the mixture and then the residue was purified by silica gel chromatography (hexane-ethyl acetate = 5: 1) to give t-butyl 6-chloromethylpyridine-2-carboxylate as a yellow powder.

¹H-NMR (CDCl₃) 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) 6-Methylpicolinic acid (2.15 g) and t-butyl piperazine-1-carboxylate (3.21 g) were dissolved in 45 ml DMF, and 4.24 g HOBt was added to the solution at ice temperature. After stirring for 15 minutes, 3.0 g WSC was added and the mixture was stirred at room temperature overnight. After removal of the solvent 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 brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - ethanol = 30: 1) to obtain 4.57 g of t-butyl 4- (6-methylpyridine-2-carbonyl) piperazin-1-carboxylate as a colorless oil.

<td>¹H-NMR (CDCl₃) δ</td><td>: 7.67 (1H, t,</td><td>J =</td><td> 7,8</td><td>Hz), 7.35</td>

<td>(1H, d, J = 7.8 Hz),</td><td>7.21 (IH, d, J</td><td> = 7,8</td><td>Hz),</td><td>3.77 (2H,</td>

<td>t, J = 4.8 Hz), 3.55</td><td>(4H, t, J = 4.8</td><td>Hz),</td><td> 3,46</td><td>(2H, t, J</td>

<td>= 4.8 Hz), 2.57 (3H,</td><td>s), 1.47 (9H, s)</td><td>_.</td><td></td><td></td>

(2) t-butyl 4- (6-methylpyridine-2-carbonyl) piperazine-1-carboxylate (4.57 g) was dissolved in 30 ml of chloroform, the solution was slowly added dropwise to the resulting solution

3.9 g m-CPBA in 40 ml chloroform. The mixture was then stirred at room temperature for one day, then 10% aqueous sodium sulfite (35 mL) was added to the reaction mixture, and the mixture was separated. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (methylene chloride ethanol = 40: 1) to give 4.2 g of t-butyl 4- (6-methyl-1-oxypyryne-2-carbonyl) piperazine-1-carboxylate in the form of white powder.

¹H-NMR (CDCl₃) δ: 7.31-7.17 (3H, m), 3.91 (1H, broad s), 3.62-3.56 (4H, m), 3.45 (1H, wide s), 3 , 26 (1H, broad s), 3.13 (1H, broad s), 2.51 (3H, s), 1.47 (9H, s).

(3) To t-butyl 4- (6-methyl-1-oxypyridine-2-carbonyl) -piperazine-1-carboxylate (4.2 g) was added 1.2 ml of acetic anhydride and the mixture was stirred at 100 ° C. within 1 hour. After cooling, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent removed under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - ethanol = 40: 1) to give 3.7 g of t-butyl 4- (6-acetoxymethylpyridine-2-carbonyl) piperazine-1-carboxylate as a colorless oil.

<td></td><td>¹H-NMR</td><td>(CDCl₃) δ</td><td>: 7.82 (1H, t,</td><td>J = 7.8</td><td>Hz), 7.6</td>

<td>(1H,</td><td>d, J =</td><td>7.8 Hz),</td><td>7.40 (IH, d, J</td><td>= 7.8 Hz),</td><td>5.22 (2H</td>

<td>s),</td><td>3.77 (2H</td><td>, t, J =</td><td>4.8 Hz), 3.59</td><td>3.56 (4H,</td><td>wide)</td>

<td> 3,69</td><td>(2H, t,</td><td>J = 4.8</td><td>Hz), 2.17 (3H, s)</td><td>, 1.47 (9H,</td><td>s).</td>

(4) To a solution of 3.7 g of t-butyl 4- (6-acetoxymethylpyridine-2-carbonyl) piperazine-1-carboxylate in 10 ml of methanol was added 840 mg of potassium hydroxide and the mixture was heated to reflux for 4 hours. After removal of the solvent, water was added to the solution and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride ethanol - 50: 1) to give 1.2 6 g of t-butyl 4- (6-hydroxymethyl-pyridine-2-carbonyl) piperazine-1-carboxylate as a colorless oil .

¹H-NMR (CDCl₃) 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, broad), 1.47 (9H, s).

(5) t-butyl 4- (6-hydroxymethylpyridine-2-carbonyl) piperazine-1-carboxylate (1.26 g) and diisopropylethylamine (1.0 g) were dissolved in 20 ml of methylene chloride, 0.1 was added dropwise to the above solution ml methanesulfonyl chloride at ice temperature 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 chromatography (methylene chloride-ethanol - 40: 1) to obtain 1.07 g of 4- (6-chloro-methylpyridine-2-carbonyl) piperazin-1-carboxylate t-butyl in the form of a colorless oil.

¹H-NMR (CDCl₃) 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, broad), 3.57-3.48 (6H, wide), 1.47 (9H, s).

Reference Example 10 (1) 6-Hydroxymethylpyridine-2-carbaldehyde (15.3 g) was dissolved in 250 ml of anhydrous DMF and 50 g (t-butoxycarbonylmethylene) triphenyl phosphate was added to the above solution, followed by stirring at room temperature for 30 minutes . The reaction mixture was poured into ice water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 300 ml of hexane-ethyl acetate (2: 1) was added to the residue, the insoluble part was filtered off. The filtrate was concentrated under reduced pressure, the residue purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to obtain 16.68 g of t-butyl 3- (6-hydroxymethylpyridin-2-yl) trans-acrylate and 5.69 g T-butyl 3- (6-hydroxymethylpyridin-2-yl) -cis-acrylate.

Trans form: colorless oil ¹H-MMR (CDCl₃) 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).

Yew form: colorless oil ¹H-NMR (CDCl₃) 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).

ethanol platinum, reduced catalyst (2) 3- (6-hydroxymethylpyridin-2-yl) -t-butyl trans-acrylate (trans form) (16.86 g) dissolved in 200 ml and 0.5 g of dioxide dioxide added to the solution the mixture was then stirred under atomospheric hydrogen pressure at room temperature for 5 hours. The catalyst was then filtered off, a second portion of platinum dioxide (0.5 g) was added and the mixture was stirred under atmospheric hydrogen pressure at room temperature for 6 hours. The reaction mixture was filtered off and the solvent removed under pressure to give 16.13 g of t-butyl 3- (6-hydroxymethylpyridin-2-yl) propionate as a light yellow oil.

¹H-NMR (CDCl₃) 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).

T-butyl 3- (6-hydroxymethylpyridin-2-yl) propionate (16.13 g) was dissolved in 200 ml of anhydrous methylene chloride and 33.8 g of carbon tetrabromide was added to the above solution, then added in small portions

21.5 g triphenylphosphine are stirred at ice temperature, and then the mixture is stirred at the same temperature for 30 minutes. The reaction mixture was transferred to a separatory funnel, washed with saturated aqueous sodium bicarbonate solution, then brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue, 200 ml of Hexane-ethyl acetate mixture (2: 1) were added, the insoluble part of the precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 5: 1) to obtain 14.12 g of t-butyl 3- (6-bromomethyl-pyridin-2-yl) propionate as a light yellow oil .

¹H-NMR (CDCl₃) 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-bromopyridine-6-methanol (2 g) was dissolved in 10 ml anhydrous DMF and 1.73 ml ethyl acrylate, 2.95 g tetra (n-butyl) ammonium chloride, 1, was added to the solution. 78 g hydrogen sodium carbonate and 2 g molecular sieves (3A molecular sieves (1/16)), then 119 mg palladium (II) acetate was added under argon and the mixture was stirred at 80 ° C for 5h. After cooling, the insoluble portion was filtered off and water was added, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to obtain 1.39 g of ethyl 3- (6-hydroxy-methylpyridin-2-yl) trans-acrylate as a light yellow oil.

¹H-KMR (CDCl₃) 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) According to the same procedure described in Reference Example 10- (2), ethyl 3- (6-hydroxymethylpyridin-2-yl) -trans-acrylate was reduced to give ethyl 3- (6-hydroxymethylpyridin-2-yl) propionate in clear form -yellow oil.

<td></td><td></td><td>¹H-NM</td><td>R</td><td>(CDCl₃) δ:</td><td>7.58 (1H, t,</td><td>J = 7.5 Hz</td><td> ), 7,08</td><td>(1H,</td>

<td>d</td><td>J</td><td> = 7,</td><td> 5</td><td>Hz), 7.02</td><td>(1H, d, J. =</td><td>7.5 Hz), 4,</td><td>71 (2H,</td><td>d, J.</td>

<td> =</td><td> 4,</td><td>5 Hz)</td><td>^,</td><td>4.14 (2H,</td><td>q, J = 7.2</td><td>Hz), 4.01</td><td>(1H, t,</td><td>J =</td>

<td> 4,</td><td> 5</td><td>Hz),</td><td> 3</td><td>, 15 (2H,</td><td>t, J = 7.5</td><td>Hz), 2.80</td><td>(2H, t,</td><td>J =</td>

<td> 7,</td><td> 5</td><td>Hz),</td><td> 1,</td><td>24 (3H, vol</td><td>, J = 7.2 Hz)</td><td>_.</td><td></td><td></td>

Reference Example 12 (1) Following the same procedure described in Reference Example 1, using methylacrylate, 3- (6-hydroxymethylpyridin-2-yl) -trans-acrylate was obtained.

<td rowspan="2">lan</td><td rowspan="2">methyl in the form¹H-NMR (CDCl₃) δ:</td><td colspan="4">pale yellow powder.</td><td rowspan="2">Hz),</td><td colspan="2" rowspan="2"> 7,68</td>

<td> 7,72</td><td>(1H,</td><td>t, J =</td><td> 7,5</td>

<td>(1H,</td><td>d, J = 15.6 Hz)</td><td> , 7,32</td><td>(1H,</td><td>d, J =</td><td> 7,5</td><td>Hz),</td><td> 7,</td><td> 21</td>

<td>(1H,</td><td>d, J = 7.5 Hz),</td><td> 6,97</td><td>(1H,</td><td>d, J =</td><td> 15,6</td><td>Hz),</td><td> 4,</td><td> 78</td>

<td>(2H,</td><td>d, J = 4.2 Hz), 3,</td><td>85 (1H,</td><td>t, J =</td><td>4.2 Hz)</td><td> , 3,</td><td>83 (3H,</td><td>s</td><td> ).</td>

(2) According to the same procedure described in Reference Example 10- (2), methyl 3- (6-hydroxymethylpyridin-2-yl) -trans-acrylate was reduced to give methyl 397 (6-hydroxymethylpyridin-2-yl) propionate in pos.

<td>TACI</td><td>light brown oil.</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>¹H-NMR (CDCl₃) δ: 7.58</td><td>(1H, t,</td><td>J =</td><td> 7,</td><td> 5</td><td>Hz),</td><td> 7,09</td>

<td>(1H,</td><td>d, J = 7.5 Hz), 7.03</td><td>(1H, d,</td><td>J =</td><td> 7,</td><td> 5</td><td>Hz),</td><td> 4,71</td>

<td>(2H,</td><td>s), 4.01 (1H, broad p</td><td> ), 3,69</td><td>(3H,</td><td>s)</td><td>^,</td><td> 3,15</td><td>(2H,</td>

<td>t, J.</td><td>= 7.2 Hz), 2.81 (2H, t,</td><td>J = 7.2</td><td>Hz).</td><td></td><td></td><td></td><td></td>

The above compound was also prepared as follows: To a solution of 50.02 g of methyl 3- (6-hydroxymethylpyridin-2-yl) -trans-acrylate in 502 ml of IPA, was added

2.51 g of 5% palladium-carbon (containing 50% water) under an argon atmosphere, the reaction mixture was stirred under an atmosphere of 1-4 hydrogen atoms at 50 ° C for 2.5 h. After cooling, the catalyst was filtered off and the reaction mixture was removed under reduced pressure to give 50 g of methyl 3- (6-hydroxymethylpyridin-2-yl) propionate as a brown oil. Reference Example 13 (1) 6-hydroxymethylpyridine-2-carbaldehyde (2.95 g) and triethyl 2-phosphonopropionate (5.12 g) were dissolved in 20 ml of anhydrous DMF and a solution of 1.30 g sodium methoxide in 10 was added dropwise to the solution. ml of methanol, after which the mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give

2.42 g of ethyl (E) -3- (6-hydroxymethylpyridin-2-yl) -2-methylacrylate as a colorless oil.

¹H-NMR (CDCl₃) 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) According to the same procedure described in Reference Example 10- (2), ethyl (E) -3- (6-hydroxymethyl-pyridin-2-yl) -2-methylacrylate was reduced to give c 3- (6-hydroxymethylpyridin-2-yl) ) Ethyl -2-methylpropionate as a colorless oil.

<td>¹H</td><td>NMR</td><td>(CDCl₃) δ</td><td>: 7.57 (1H,</td><td>t</td><td>J = 7.5 Hz), 7.04</td>

<td>(1H, d,</td><td>J =</td><td>7.5 Hz),</td><td>7.02 (1H, d,</td><td>J =</td><td>7.5 Hz), 4.70 (2H,</td>

<td>wide</td><td>s),</td><td>4.11 (2H,</td><td>q, J = 7.2</td><td>Hz),</td><td>3.22 (IH, dd, J =</td>

<td> 14,1, 7</td><td> ,8</td><td>Hz), 3.05</td><td>(1H, sextet</td><td>, J</td><td>= 6.3 Hz), 2.88 (1H,</td>

dd, J = 14.1, 6.3 Hz), 1.27-1.16 (6H, m).

Reference Example 14

To the solution prepared from t-butyl 3- (6-hydroxymethylpyridin-2-yl) -trans-acrylate (trans form, 2 g) described in Reference Example 10- (1) and carbon tetrabromide (4.23 g) in methylene chloride (20 mL) at ice temperature, triphenylphosphine (2.68 g) was added in small portions, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was transferred to a separatory funnel, diluted with chloroform, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate = 10: 1) to obtain 2.23 g of t-butyl 3- (6-bromo-methylpyridin-2-yl) -trans-acrylate in postsci slightly yellow powder.

<td></td><td>¹H-NMR (CDCl₃)</td><td>δ: 7.70 (</td><td>1H, t,</td><td>J =</td><td>7.8 Hz), 7.56 (1H, d,</td>

<td>J =</td><td>15.6 Hz), 7.41</td><td>(1H, d, J</td><td> = 7,8</td><td>Hz),</td><td>7.32 (IH, d, J = 7.8</td>

<td>Hz),</td><td>6.87 (IH, d, J</td><td>= 15.6 Hz)</td><td> , 4,54</td><td>(2H,</td><td>s), 1.53 (9H, s).</td>

Reference Example 15 (1) 4-Pentic acid (1.03 g) and N-methylpiperazine (1.0 g) were dissolved in 30 ml DMF, added to the solution with stirring.

1.6 g HOBt at ice temperature. The mixture was stirred at the same temperature for 15 minutes, then 2.3 g of WSC was added and the solution was stirred at room temperature overnight. DMF was removed from the reaction mixture under reduced pressure, then water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine = 600: 20: 1) to obtain 510 mg of 1- (4-methyl-piperazin-1-yl) pent-4-yn-1-one as a colorless oil.

¹H-NMR (CDCl₃) 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) Into a 50-ml round-bottom flask, 484 mg of 2-bromopyridine-6-methanol, 510 mg of 1- (4-methylpiperazin-1-yl) pent-4-yn-1-one, 20 mg BHT, 162 mg copper iodide were introduced (I), 118 mg tetrakis (triphenylphosphine) palladium (0), 375 mg t-butylamine and

7.5 ml DMF and the mixture was stirred under argon at 80 ° C for 6 hours. DMF was removed under reduced pressure, then a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine = 600: 20: 1) to obtain 540 mg of 5- (6-hydroxymethyl-pyridin-2-yl) -1- (4-methyl-piperazin-1-yl) pent-4 -yn-1-one in the form of a yellow oil.

100 ¹H-NMR (CDCl₃) 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) To a 200 mL round-bottomed flask was added

3.49 g 2-bromopyridine-6-methanol, 3.0 g tbutyl 4-pentinate, 190 mg BHT, 1.17 g copper (I) iodide, 877 mg tetrakis- (triphenylphosphine) palladium (O), 2.72 g of t-butylamine and 56 ml of DMF and the mixture was stirred under argon at 80 ° C for 6 hours. After removing DMF from the reaction mixture under reduced pressure, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (n-hexane - ethyl acetate = 2: 1) to give 2.76 g of t-butyl 5- (6-hydroxymethylpyridin-2-yl) pent-4-ynoate as a yellow oil.

¹H-NMR (CDCl₃) 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-bottomed flask was added

2.76 g of t-butyl 5- (6-hydroxymethylpyridin-2-yl) pent-4-ynoate, 50 mg of platinum dioxide and 25 ml of EtOH, the mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. Insoluble substances were removed and the filtrate was concentrated to give 2.78 g of t-butyl 5- (6-hydroxymethylpyridin-2-yl) pentanoate as a yellow oil.

101 ¹ H-NMR (CDCl₃) 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) To a 200-mL round-bottomed flask, 50 mL of dichloromethane, 2.78 g of t-butyl 5- (6-hydroxymethylpyridin-2-yl) pentanoate and 2.0g of diisopropylethylamine were added, and the mixture was stirred at ice temperature for 10 minutes.

0.89 mL of methanesulfonyl chloride was added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was separated. The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (n-hexane - ethyl acetate = 3: 1) to obtain

2.28 g of t-butyl 5- (6-methanesulfonyloxymethylpyridin-2-yl) pentanoate in the form of a yellow oil.

¹ H-NMR, (CDCl₃) 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) Following the same procedure as described in Reference Example 11, using ethyl vinyl ketone instead of ethyl acrylate, (E) -1- (6-hydroxymethylpyridin-2-yl) pent-1-en-3-one was obtained in the form colorless oil.

<td>¹H-NMR</td><td>(CDCl₃)</td><td>δ:</td><td> 7,72</td><td>(1H,</td><td>t</td><td>J =</td><td> 7,5</td><td>Hz),</td><td> 7,55</td>

<td>(1H, d, J</td><td> = 15,6</td><td>Hz),</td><td> 7,36</td><td>(1H,</td><td>d</td><td>J =</td><td> 7,5</td><td>Hz),</td><td> 7,23</td>

<td>(1H, d, J</td><td> = 15,6</td><td>Hz),</td><td> 7,22</td><td>(1H,</td><td>d</td><td>J =</td><td> 7,5</td><td>Hz),</td><td> 4,79</td>

102 (2H, d, J = 4.5 Hz), 3.84 (1H, broad t, J = 4.5 Hz),

2.74 (2H, q, J = 7.2 Hz), 1.18 (3H, t, J = 7.2 Hz).

(2) According to the same procedure described in Reference Example 10- (2), (E) -1- (6-hydroxy -methylpyridin-2-yl) pent-1-en-3-one was reduced to c 1- (6-hydroxymethylpyridin-2-yl) pentan-3-one in the form of a light brown oil.

¹H-NMR (CDCl₃) 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, wide 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 each compound obtained according to the above Reference Examples 1-17- (2) are shown in the following summary in Table 1. Abbreviations from the tables are listed below. Abbreviations used in other tables have the same meaning.

MeO and OMe: methoxy,

Me: methyl,

Et: ethyl,

Acp and OAc: acetyloxy,

TBDMS: tert-butyldimethylsilyl,

OEt and EtO: ethoxy,

OtBu and tBuO: tert-butyloxy,

Ac: acetyl, tBu and t-Bu: tert-butyl, n-Pr: n-propyl, iPr and i-Pr: isopropyl,

Ph: phenyl, n-Bu: n-butyl, i-Bu: 2-methylpropyl.

103

Table 1

Example

Reference

No.

Structure

Meo

<img file="PL1740574T3_D0080.tif" />

<img file="PL1740574T3_D0081.tif" />

NH

M

<img file="PL1740574T3_D0082.tif" />

4-(1

CH

HO

4-(2

4-(3

HO

cl

<img file="PL1740574T3_D0083.tif" />

N

ABOUT

<img file="PL1740574T3_D0084.tif" />

N

ABOUT

104

<img file="PL1740574T3_D0085.tif" />

105

<img file="PL1740574T3_D0086.tif" />

106

<img file="PL1740574T3_D0087.tif" />

107

<img file="PL1740574T3_D0088.tif" />

108

<img file="PL1740574T3_D0089.tif" />

109

<img file="PL1740574T3_D0090.tif" />

Example 1

285 mg of the compound of Reference Example 2, 172 mg 2- (chloromethyl) pyridine hydrochloride, 184 mg sodium bicarbonate and 157 mg sodium iodide were added to DMF (3 mL) and the ingredients were 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 brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - ethanol = 40: 1) to obtain 31 mg of N- {4- [6 amino-5-cyano-2- (pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide in the form of a white powder.

¹H-NMR (DMSO-d₆) 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 = 7.8 Hz), 7.26 (1H, dd, J = 6.6, 4.8 Hz), 4.50 (2H, s), 2 , 08 (3H, s).

Example 2

6-methyl-2-pyridinomethanol (5 g) was dissolved in 50 mL of methylene chloride and 10.6 mL of diisopropylethylamine was added to the solution, followed by the dropwise addition of 3.5 mL of methanesulfonyl chloride under ice stirring. After stirring at ice temperature for 1 hour, water was added to the reaction solution, followed by washing the organic layer with water (2x) and brine (1x). The organic layer was dried over magnesium sulfate, and then the solvent was removed to give 6.98 g of a brown oil.

110

Part of the product (4.56 g) was dissolved in 50 ml of ethanol, 1.72 g of thiourea was added to the solution, and the mixture was heated to reflux for 1 hour. Then 20 ml of ethanol was added to the reaction solution, and the solution was cooled, then 4.79 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 3 g of sodium bicarbonate were added, and the mixture was heated to reflux within 1.5 hours. The reaction solution was allowed to cool, then 2.02 g of NBS was added to the solution, and the mixture was heated to reflux for 30 minutes. The solution was allowed to cool, diisopropylether was added, the precipitated inorganic substances were filtered off, then the filtrate was again concentrated and dissolved in ethanol. Saturated aqueous sodium bicarbonate solution was added to the solution and the resulting crystals were filtered off, washed with water and ethanol, and then dried under reduced pressure to obtain 3.2 g of N- {4- [6-amino-5-cyano-2 (6-methylpyridin-2 -ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide in the form of a white powder.

<td>¹H-NMR (DMSO-d₆)</td><td>δ:</td><td> 10,2</td><td>(IH, s), 7.83</td><td>(2H d, J = 8.7</td>

<td>Hz), 7.72 (2H, d, J =</td><td colspan="2">8.7 Hz),</td><td>7.60 (IH, t, J</td><td>= 7.5 Hz), 7.33</td>

<td>(1H, d, J = 7.5 Hz),</td><td> 7,12</td><td>(1H,</td><td>d, J = 7.5 Hz)</td><td>, 4.44 (2H, s),</td>

2.45 (3H, s), 2.09 (3H, s).

Example 3

Following the same procedure described in Example 2, using 5-methyl-2-pyridine methanol instead of 6-methyl-2-pyridine methanol gave N- {4- [6-amino-5-cyano-2- (5-methylpyridin-2-ylmethylsulfanyl) pyrimidine -4-yl] phenyl} acetamide in the form of a white powder.

¹H-NMR (DMSO-d₆) δ: 10.23 (1H, s), 8.34 (1H, s), 7.60-8.20 (2H, broad 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).

111

Example 4

By the same procedure described in Example 2, using 4-methyl-2-pyridinomethanol instead of 6-methyl-2-pyridinomethanol, N- {4- [6-amino-5-cyano-2- (4-methyl-pyridinium- 2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide as a slightly yellow powder.

¹H-NMR (DMSO-d₆) δ: 10.24 (1H, s), 8.62 (1H, s), 7.65-8.25 (2H, wide 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).

Example 5

Following the same procedure described in Example 2, using 3-methyl-2-pyridinomethanol instead of 6-methyl-2-pyridinomethanol, N- {4- [6-amino-5-cyano-2- (3-methylpyridin-2-ylmethylsulfanyl) was obtained pyrimidin-4-yl] phenyl} acetamide in the form of a white powder.

<td></td><td>¹H-NMR (DMSO-d₆)</td><td>δ: 10.24</td><td>(1H, s),</td><td> 8,34 (</td><td>1H,</td><td>d, J = 4.8</td>

<td>Hz),</td><td>7.70-8.25 (2H,</td><td>wide s)</td><td> , 7,87</td><td>(2H, d,</td><td>J</td><td>= 8.7 Hz),</td>

<td> 7,73</td><td>(2H, d, J = 8.7</td><td>Hz), 7.60</td><td colspan="2">(1H, d, J = 7.5</td><td>Hz)</td><td> , 7,19-7,24</td>

<td>(1H,</td><td>m), 4.61 (2H, s)</td><td>, 2.36 (3H,</td><td colspan="2">s), 2.09 (3H, s)</td><td>_.</td><td></td>

Example 6

Following the same procedure described in Example 2, using 1- (6-methylpyridin-2-yl) ethanol instead of 6-methyl-2-pyridinomethanol, N- (4- {6-amino-5-cyano-2- [1- ( 6-methylpyridin-2-yl) ethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide as a white powder.

¹H-NMR (CDCl₃) δ: 10.25 (1H, broad s), 7.83 (2H, d, J =

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).

112

Example 7

Following the same procedure described in Example 2, using 1- (6-methylpyridin-2-yl) pentan-1-ol instead of 6-methyl-2-pyridinamethanol, N- (4- {6-amino-5-cyano-2 [ 1- (6-methylpyridin-2-yl) pentylsulfanyl] pyrimidin-4-yl} phenyl) -acetamide as a white powder.

¹H-NMR (CDCl₃) δ: 8.40 (1H, broad s), 7.94 (2H, d, J = 6 Hz), 7.63 (2H, d, J = 6 Hz), 7.52 (1H, t, J = 6 Hz), 7.22 (1E, d, J = 6 Hz), 7.00 (1H, d, J = 6 Hz), 5.79 (1H, wide s), 5.03 (1H, t , J = 6 Hz), 2.55 (3H, s), 2.21 (3H, s), 2.002.15 (2H, m), 1.20-1.45 (4H, m), 0.86 (3H, t, J = 6 Hz).

Example 8

The compound (5.5 g) of Example 2 was suspended in a mixture of 50 mL of ethanol and 50 mL of water, 50 mL of 5N hydrochloric acid was added to the suspension and the resulting mixture was heated with stirring at 80 ° C for 5 hours. After cooling the reaction mixture, ethanol was removed under reduced pressure, and the residue was neutralized with 5N aqueous sodium hydroxide solution at ice temperature. The resulting crystals were filtered and recrystallized from ethanol to give 2.3 g of 4-amino-6- (4-aminophenyl) -2- (6-methylpyridin-2-ylmethylsulfanyl) pyrimidine-5-carbonitrile as a slightly yellow powder.

<td></td><td>¹H-NMR (DMSO-d₆)</td><td>δ: 7.48-7.98 (</td><td>2H, wide</td><td>s), 7.74</td><td>(2H,</td>

<td>d</td><td>J = 8.7 Hz), 7.60</td><td>(1H, t, J = 7.8</td><td>Hz), 7.32 (</td><td>1H, d, J =</td><td> 7,8</td>

<td>Hz)</td><td>, 7.12 (1H, d, J =</td><td>7.8 Hz), 6.61</td><td>(2H, d, J =</td><td>8.7 Hz),</td><td> 5,90</td>

<td>(2H, s), 4.44</td><td>(2H, s), 2.45</td><td>(3H,</td><td>s).</td>

<td>Example 9</td><td></td><td></td><td></td>

<td>Relationship</td><td>from Example 8</td><td> (170</td><td>mg) and triethylamine (0.2 mL)</td>

<td>added to 10</td><td colspan="2">ml acetonitrile,</td><td>0.12 g was added dropwise to the solution</td>

propionyl chloride, and then the mixture was stirred at room temperature overnight. The resulting crystals were filtered, washed with diethyl ether and then dried under

113 under reduced pressure to obtain 85 mg of N- {4- [6-amino-5-cyano2- (6-methylpyridin-2-ylmethylsulfanyl) -pyrimidin-4-yl] -phenyl} -propionamide as a white powder.

<td></td><td>¹H-NMR</td><td>(DMSO-d₆)</td><td>δ: 10.16 (1H, s), 7.84</td><td>(2H, d, J = 8.7</td>

<td>Hz),</td><td> 7,74 (</td><td>2H, d, J</td><td>= 8.7 Hz), 7.61 (1H, t, J</td><td>= 7.8 Hz), 7.33</td>

<td>(1H,</td><td>d, J =</td><td>7.8 Hz),</td><td>7.12 (1H, d, J = 7.8 Hz)</td><td>, 4.45 (2H, s),</td>

2.45 (3H, s), 2.37 (2H, q, J = 8.7 Hz), 1.10 (3H, t, J = 7.5 Hz). Example 10

Following the same procedure described in Example 9, using acryloyl chloride instead of propionyl chloride gave N- {4- [6-amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl) -pyrimidin-4-yl] phenyl} acrylamide in the form of a white powder.

¹H-NMR (DMSO-d₆) 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). Example 11

Following the same procedure described in Example 9, using butyryl chloride instead of propionyl chloride gave N- {4- [6-amino-5-cyano-2- (6-methylpyridin-2-ylmethylsulfanyl) -pyrimidin-4-yl] phenyl} butylamide in white powder forms.

<td></td><td>¹H</td><td>NMR (DMSO-d₆)</td><td>δ: 10.17 (1H,</td><td>s), 7.65-8.20</td><td>(2H,</td><td>wide</td>

<td>s),</td><td> 7,83</td><td>(2H, d, J =</td><td>8.7 Hz), 7.74</td><td>(2H, d, J = 8</td><td>, 7 Hz</td><td> ), 7,61</td>

<td>(1H,</td><td>t</td><td colspan="2">J = 7.8 Hz), 7.33 (1H, d, J</td><td>= 7.8 Hz), 7.12</td><td>(1H,</td><td>d, J =</td>

<td> 7,8</td><td>Hz),</td><td>4.45 (2H, s)</td><td>, 2.45 (3H, s)</td><td>, 2.33 (2H, t,</td><td>J =</td><td>7.5Hz)</td>

<td> 1,63</td><td>(3H</td><td>, sext, J =</td><td>7.5 Hz), 0.93 (</td><td>3H, t, J = 7,</td><td>5Hz).</td><td></td>

<td>At</td><td>Quad</td><td> 12</td><td></td><td></td><td></td><td></td>

Following the same procedure described in Example 9, using benzoyl chloride instead of propionyl chloride gave N- {4- [6-amino-5-cyano-2- (6-methylpyridin-2114 ylmethylsulfanyl) -pyrimidin-4-yl] phenyl} benzamide in the form of a white powder.

¹H-NMR (DMSO-d₆) 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 = 7.5 Hz), 4.47 (2H, s), 2.46 (3H, s).

Example 13

Following the same procedure described in Example 2, using 6-methyl-2-pyridine methanol, thiourea and the compound of Reference Example 1, (4- [6-amino-5-cyano-2- {610 methylpyridin-2-ylmethylsulfanyl) pyrimidine was obtained Methyl-4-yl] phenyl} carbamate as a yellow powder.

¹H-NMR (DMSO-d₆) 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 each compound obtained according to Examples 1-13 above are shown in Table 2 below.

Table 2

N

<img file="PL1740574T3_D0091.tif" />

_R3

115

<img file="PL1740574T3_D0092.tif" />

116

<img file="PL1740574T3_D0093.tif" />

Example 14

Compound of Reference Example 2 (10 g), compound of Reference Example 3 (9.8 g), sodium bicarbonate (3.52 g) sodium iodide (5.40 g) was added to 100 mL DMF, the resulting mixture was stirred at room temperature at during the night. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - ethanol - triethylamine 800: 40: 1) to give 1.67 g of N- {4- [6-amino-5-cyano-2- (6-morpholin-4-ylmethylpyridin-2- ylometylosul-phenylsulfanyl) -2,3dihydropirymidyn-4-yl] phenyl} acetamide.

The above compound (600 mg) was dissolved in 12 mL of 1,4-dioxane, 290 mg of DDQ was added to the solution, and the mixture was heated to reflux for 2 hours. After

117 removing the solvent, water was added to the residue, and hydrochloric acid was added to acidify the solution. The resulting solution was washed with ethyl acetate, the aqueous layer was basified with 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was crystallized 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.

All of the above product was dissolved in ethanol, 1 mol / L hydrochloric acid in ethanol (0.61 mL) was added thereto, and the mixture was evaporated to dryness in vacuo to afford

<td rowspan="2">hydrochloride ¹H-NMR (</td><td rowspan="2">of the above compound DMSO-d₆) δ: 10.2 (1H,</td><td rowspan="2">in the form s), 7.82 (</td><td colspan="3">white powder.</td>

<td>2H,</td><td>d, J = 8.7</td><td>Hz),</td>

<td>7,72-7,67 (3H,</td><td>m), 7.40 (1H, d, J = 7.8</td><td>Hz), 7.31</td><td>(1H,</td><td>d, J = 7.8</td><td>Hz),</td>

<td>4.47 (2H, s),</td><td>3.57 (4H, broad</td><td>t), 2.39 (</td><td>4H,</td><td>wide</td><td>t),</td>

2.08 (3H, s).

Example 15

To a solution of the compound of Reference Example 2 (287 mg) in 3 ml DMF was added the compound of Reference Example 4 (260 mg), sodium bicarbonate (100 mg) and sodium iodide (150 mg) and the mixture was stirred at room temperature overnight . After adding water to the reaction mixture, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. To the residue, 1 ml of acetonitrile and 7.3 mg of NBS were added and the mixture was heated to reflux for 30 minutes. After cooling the reaction mixture, water was added and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was crystallized from ethanol to give 35 mg of N- (4- {6-amino-5-cyano-2- [6- (2-morpholin-4-ethylethyl) -pyridin-2-ylmethylsulfanyl] -pyrimidin-4-yl} -phenyl) acetamide. All the resulting compound was dissolved in ethanol, 1 mol / L hydrochloric acid in ethanol (0.14 mL) was added, and the mixture was evaporated to dryness under reduced pressure to give 40 mg of the desired compound as the hydrochloride as a white powder.

<td>¹H-NMR</td><td>(DMSO-d₆) δ: 10.2 (</td><td>1H, p</td><td> ), 7,83 (</td><td>2H, d,</td><td>J =</td><td> 8,7</td>

<td>Hz), 7.71 (</td><td>2H, d, J = 8.7 Hz),</td><td> 7,66 (</td><td>1H, t, J</td><td> = 7,2</td><td>Hz),</td><td> 7,33</td>

<td>(1H, d, J =</td><td>7.2 Hz), 7.15 (1H,</td><td>d, J =</td><td>7.2 Hz)</td><td> , 4,46</td><td>(2H,</td><td>s),</td>

<td> 3,55-3,52 (</td><td>4H, m), 2.86 (2H, vol</td><td>, J =</td><td>7.2 Hz),</td><td> 2,60</td><td>(2H,</td><td>t, J.</td>

<td>= 7.2 Hz), 2</td><td>, 39 (4H, wide t)</td><td> , 2,03</td><td>(3H, s).</td><td></td><td></td><td></td>

Example 16

Thiourea (86 mg) and the compound of Reference Example 5 (290 mg) 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 further added to the solution and heated to reflux for 5 hours. After allowing to cool, further 200 mg of NBS were introduced and the mixture was heated to reflux for 1 hour. Water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (chloroform methanol - aqueous ammonia = 300: 10: 1) to obtain 85 mg of N- (4- {6-amino-5-cyano-2- [6- (3-morpholin-4- ylpropylo) pyridin-2ylometylosulfa nyl] pyrimidin-4-yl} phenyl) acetamide.

All the resulting compound was dissolved in ethanol, added to a solution of 1 mol / L hydrochloric acid in ethanol (0.38 mL), and then the solvent was removed to give 110 mg of the hydrochloride of the desired compound as a yellow powder.

119 ¹H-NMR (DMSO-d₆) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz),

<td>7.71 (2H</td><td>, d, J = 8.7 Hz), 7.61 (1H, t,</td><td>J = 7.5 Hz)</td><td> , 7,32</td><td>(1H, d,</td>

<td>J = 7.5</td><td>Hz), 7.12 (1H, d, J = 7.5 Hz)</td><td>, 4.40 (2H,</td><td>s), 3,</td><td> 64-3,50</td>

<td>(4H, m),</td><td>2.70 (2H, t, J = 7.5 Hz),</td><td> 2,40-2,24</td><td>(6H, m</td><td> ), 2,08</td>

<td>(3H, s),</td><td>2.49-2.45 (2H, m).</td><td></td><td></td><td></td>

<td>Example</td><td> 17</td><td></td><td></td><td></td>

Compound of Reference Example 6 (15 g) and thiourea (3.8 g) were suspended in 200 ml of ethanol and the suspension was stirred at 60 ° C for 1 hour. 9.72g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide was added to the reaction mixture, and the mixture was heated to reflux overnight. After removal of the solvent under reduced pressure, water was added to the residue, the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - methanol - aqueous ammonia = 300: 10: 1) to obtain 10.3 g 4- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyano pyrimidin-2-ylsulfanyl-methyl] pyridin-2-ylmethyl} piperazin-1-carboxylate t-butyl as a white powder.

<td></td><td>¹H-NMR</td><td>(DMSO-d₆)</td><td>δ</td><td> : 10,2</td><td>(1H, s), 7.83 (2H,</td><td>d, J = 8.7</td>

<td>Hz)</td><td> , 7,72-7,</td><td>70 (3H, m)</td><td>^,</td><td> 7,40 (</td><td>1H, d, J = 7.5 Hz),</td><td>7.32 (1H, d,</td>

<td>J =</td><td>7.5 Hz),</td><td>4.47 (2H,</td><td>s)</td><td> , 3,57</td><td>(2H, s), 2.50-2.35 (</td><td>8H, m), 2.20</td>

(3H, s), 1.38 (9H, s).

Example 18

The compound of Example 17 (123 mg) was added to a round bottom flask and 0.35 mL of trifluoroacetic acid was added at ice temperature. The mixture was stirred at room temperature for 1 hour, and then trifluoroacetic acid was removed under reduced pressure. 0.1 mol / L was added to the residue

120 hydrochloric acid in 6 ml of ethanol and the solvent was evaporated till dryness. The remaining solid product was crystallized from ethanol to give 80 mg of N- {4- [6-amino-5-cyano-2- {6-piperazin-1-yl-methylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} -acetamide as the hydrochloride salt white powder forms.

¹H-NMR (DMSO-d₆) δ: 10.3 (1H, s), 9.42 (1H, broad s),

<td> 7,89-7,81</td><td>(3H,</td><td>m),</td><td> 7,73</td><td>(2H, d, J =</td><td>8.7Hz)</td><td> , 7,63</td><td>(1H, d, J =</td>

<td>7.5 Hz), 7</td><td> ,52 (</td><td>1H,</td><td>d, J.</td><td>= 7.5 Hz),</td><td> 4,55</td><td>(2H, s)</td><td> , 3,37-3,25</td>

<td>(10H, m),</td><td> 2,03</td><td>(3H,</td><td>s).</td><td></td><td></td><td></td><td></td>

Example 19

The compound of Example 18 (292 mg), benzoic acid (61 mg) and triethylamine (0.2 mL) were dissolved in 3 mL DMF, 80 mg HOBt was added to the above solution with stirring at ice temperature. After stirring the mixture at the same temperature for 15 minutes, 115 mg of WSC were added and the mixture was stirred at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure, and ice-water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine = 300: 10: 1) to obtain 261 mg of N- (4 {6-amino-2- [6- (4-benzoylpiperazin-1-ylmethyl) pyridine -2-methylmethylsulfanyl] -5-cyanopyrimidin-4-yl} -phenyl) acetamide as a white powder.

¹H-NMR (DMSO-d₆) 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).

Example 20

The compound of Example 18 (146 mg), benzaldehyde (28 mg) and triethylamine (75 mg) were dissolved in a mixture of 1 ml DMF and 2

121 ml of methanol, the resulting mixture was stirred at room temperature overnight. 30 mg of sodium cyanoborohydride were added to the reaction mixture at ice temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, ice water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine = 600: 20: 1) to obtain 60 mg of N- (4- {6-amino-2- [6- (4-benzylpiperazin-1-ylmethyl) pyridin-2- ylmethylsulfanyl-3-5-cyanopyrimidin-4-yl} phenyl) acetamide as a white powder.

¹H-NMR (DMSO-d₆) 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).

Example 21

Following the same procedure described in Example 19, using (4-methylpiperazin-1-yl) acetic acid instead of benzoic acid, N- {4- [6-amino-5-cyano-2 hydrochloride (6- {4- [2 - (4-methylpiperazin-1-yl) acetyl] piperazin-1-ylmethyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide as a white powder.

¹H-NMR (DMSO-d₆) 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, broad 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).

122

Example 22

Following the same procedure described in Example 19, using p-methoxybenzoic acid instead of benzoic acid, N- [4- (6-amino-5-cyano-2- {6- [4- (4-methoxy-benzoyl) piperazin-1 hydrochloride was obtained -ylmethyl] pyridin-2-methylsulfanyl} pyrimidin-4-yl) phenyl] acetamide in the form of a white powder.

¹H-NMR (DMSO-d₆) 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), 2.492.45 (4H, m) , 2.08 (3H, s).

Example 23

Following the same procedure described in Example 19, using N, N-dimethylglycine instead of benzoic acid, N- [4- (6-amino-5-cyano-2- {6- [4- (2-dimethylaminoacetyl) piperazine- 1-ylmethyl] pyridin-2-methylsulfanyl} pyrimidin-4-yl) phenyl] acetamide in the form of a white powder.

¹H-HMR (DMSO-d₆) δ: 10.2 (1H, s), 7.83 (2H, d, J = 9.0

<td>Hz),</td><td>7.72-7.68 (3H,</td><td>m),</td><td> 7,42</td><td>(1H,</td><td>d, J.</td><td>= 7.5 Hz), 7.33 (1H, d,</td>

<td>J =</td><td>7.5 Hz), 4.48</td><td>(2H,</td><td>s),</td><td> 3,59</td><td>(2H,</td><td>s), 3.49-3.41 (4H, m),</td>

<td> 3,15</td><td>(2H, wide</td><td>s),</td><td> 2,48-</td><td> 2,42</td><td>(4H,</td><td>m), 2.21 (6H, s), 2.08</td>

(3H, s).

Example 24

Following the same procedure described in Example 19, using piperidine-1-propionic acid instead of benzoic acid, N- [4- {6-amino-5-cyano-2- {6- [4- (3-piperidin-1-ylpropionyl hydrochloride) was obtained. ) piperazin-1-ylmethyl] pyridin-2-methylsulfanyl} pyrimidin-4-yl) phenyl] acetamide as a white powder.

123 ¹H-NMR (DMSO-d₆) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7

<td></td><td colspan="2">Hz), 7.74-7.68 (3H, m), 7.43</td><td>(1H,</td><td>t, J = 7.5 Hz), 7.33 (1H, d,</td>

<td></td><td>J = 7.5 Hz</td><td>), 4.47 (2H, s),</td><td> 3,60</td><td>(2H, s), 3.44-3.34 (4H, m),</td>

<td></td><td> 2,51-2,50 (</td><td>4H, m), 2.43-2.37</td><td>(4H,</td><td>m), 2.09 (3H, s), 1.58 (4H,</td>

<td> 5</td><td>wide s),</td><td>1.43 (2H, broad</td><td>t).</td><td></td>

Example 25

Following the same procedure described in Example 19, using piperidin-1-ylacetic acid instead of benzoic acid, N- [4- (6-amino-5-cyano-2- {6- [4- (210 piperidin-1- ylacetyl) piperazin-1-ylmethyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide as a white powder.

¹H-NMR (CD₃0D) 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 15 (2H, s), 4.55 (2H , s), 4.42 (2H, s), 3.92 (1H, broad s), 3.773.72 (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 each compound obtained according to Examples 14-25 are shown in Table 3 below.

Table 3

N

<img file="PL1740574T3_D0094.tif" />

NR 3

124

<td>Example No.</td><td>R³ =</td>

<td> 14</td><td></td>

<td> 15</td><td></td>

<td> 16</td><td>about</td>

<td> 17</td><td>k / ky</td>

<td> 18</td><td>k./···</td>

<td> 19</td><td>k / k / '^ph</td>

<td> 20</td><td>^^ and ^^ N Ph</td>

<td> 21</td><td>^ yome</td>

<td> 22</td><td>ome about</td>

125

<td> 23</td><td>_ABOUT^NMe</td>

<td> 24</td><td></td>

<td> 25</td><td>^ 'Ro</td>

Example 26

The compound of Reference Example 7 (571 mg) and thiourea (180 mg) were dissolved in 20 ml of ethanol and the 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 resulting mixture was heated to reflux for 4 hours. After cooling the reaction mixture, 356 mg of NBS were added and the resulting mixture was heated to reflux for 1 hour. After cooling, 5 ml of saturated aqueous sodium bicarbonate solution and 10 ml of water were added, the precipitate was filtered off, washed with water and dried under reduced pressure to obtain 380 mg of N- (4- {6-amino-5-cyano-2- hydrochloride [6 - (morpholine-4-carbonyl) pyridin-215 ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide in the form of a white powder.

<td></td><td>¹H-NMR (DMSO-d₆)</td><td>δ:</td><td> 10,2</td><td>(IH, s), 7.86</td><td>(1H, t, J = 7.8</td>

<td>Hz),</td><td>7.79 (2H, d, J =</td><td colspan="2">9.0 Hz),</td><td>7.70 (2H, d, J</td><td>= 9.0 Hz), 7.62</td>

<td>(1H,</td><td>d, J = 7.8 Hz),</td><td> 7,47</td><td>(1H,</td><td>d, J = 7.8 Hz</td><td>), 4.53 (2H, s),</td>

<td> 20 3,63</td><td>(4H, wide t),</td><td colspan="2"> 3,49-3,44</td><td>(2H, m), 2.08 (</td><td>3H, s).</td>

126

Example 27

Following the same procedure described in Example 26, using the compound of Reference Example 8 instead of the compound of Reference Example 7, 6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine-2- pyridine-2- t-butyl carboxylate in the form of a white powder.

¹H-NMR (DMSO-d₆) δ: 7.82-7.72 (7H, m), 4.55 (2H, s), 2.08 (3H, s), 1.54 (9H, s).

Example 28

Following the same procedure described in Example 26, using the compound of Reference Example 9 instead of the compound of Reference Example 7, 4- {6- [4- (4-acetylamino-phenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine-2 was obtained t-butyl carbonyl} piperazin-1-carboxylate in the form of a white powder.

<td></td><td>¹H-NMR (DMSO-d₆)</td><td>δ: 10.2 (1H</td><td>, s),</td><td>7.89 (IH, vol</td><td>, J = 7.8</td><td>Hz),</td>

<td> 7,83</td><td>(2H, d, J = 8.7</td><td>Hz), 7.75</td><td>(2H,</td><td>d, J = 8.7</td><td>Hz), 7.63</td><td>(1H,</td>

<td>d, J.</td><td>= 7.8 Hz), 7.47</td><td>(1H, d, J</td><td> = 7,8</td><td>Hz), 4.53</td><td>(2H, s),</td><td> 3,60-</td>

<td> 3,56</td><td>(2H, wide),</td><td> 3,45-3,31</td><td>(6H,</td><td>wide),</td><td>2.09 (3H,</td><td>s),</td>

<td colspan="3">1.40 (12H, s). Example 29 To the relationship of Example 28</td><td> (600</td><td colspan="2">mg) at a temperature of</td><td>ice</td>

2 ml TFA was added, and the mixture was stirred at room temperature for 1 hour. The residual TFA was removed under reduced pressure, 20 ml 0.1 mol / L hydrochloric acid in ethanol was added to the residue, and the mixture was stirred. The obtained crystals were filtered off to obtain 80 mg of N- (4- {6-amino-5-cyano-2- [6- (piperazin-1-carbonyl) pyridin-2-ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide hydrochloride as a white powder .

127 ¹H-NMR (DMSO-d₆) δ: 10.2 (1H, s), 9.16 (2H, wide), 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, wide), 3.70 (2H, wide), 3.20-3.10 (4H, wide), 2.09 (3H, s).

The structures of each compound obtained according to Examples 26-29 are shown in Table 4 below.

Table 4

NHAc

N

<img file="PL1740574T3_D0095.tif" />

R

<td>Example No.</td><td>R =</td>

<td> 26</td><td>ABOUT /</td>

<td> 27</td><td>^ OtBu</td>

<td> 28</td><td> \_FROM-_Vfrom'·-·</td>

<td> 29</td><td>AND^nh</td>

128

Example 30 t-butyl (6-hydroxymethylpyridin-2-ylmethyl) carbamate (1 g) and diisopropylethylamine (1.1 mL) were dissolved in 20 mL of dichloromethane, 0.33 mL of methanesulfonyl chloride was added dropwise to the solution at room temperature. 1 hour at the same temperature. Water was added to the reaction solution, the organic layer was washed with water (twice) and brine (once) and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, the resulting oil was dissolved in 25 mL of ethanol together with 0.32 g of thiourea, and then heated to reflux for 1 hour. 0.4 g NBS was added to the reaction mixture, and the mixture was heated to reflux for 5 minutes. After allowing to cool, the solvent was removed. The residue was dissolved in chloroform, washed with water (twice) and brine (once), and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (methylene chloride - methanol - aqueous ammonia = 90: 10: 1). The obtained crude crystals were purified by recrystallization from ethyl acetate-hexane to give 0.97 g of t-butyl {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-methyl}} carbamate white powder.¹H-NMR (DMSO-d₆) δ: 10.25 (1H, s), 8.25-1.49 (2H, broad

<td>s), 7.98 (</td><td>1H, t,</td><td>J = 7.5 Hz</td><td> ), 7,83</td><td>(2H, d,</td><td>J = 8.7</td><td>Hz),</td><td> 7,73</td>

<td>(2H, d, J</td><td> = 8,7</td><td>Hz), 7.64</td><td>(1H, d,</td><td>J = 7</td><td>, 5 Hz),</td><td> 7,53</td><td>(1H,</td>

<td>broad s) d, J = 5.7</td><td>, 7.33 Hz), 2,</td><td>(1H, d, J 09 (3H, s),</td><td colspan="2">= 7.5 Hz), 4.54 1.40 (9H, s).</td><td>(2H, s),</td><td> 4,29</td><td>(2H,</td>

Example 31

To 0.2 g of the compound of Example 30, 1 ml of trifluoroacetic acid was added, and the mixture was stirred for 30 minutes at room temperature, followed by removal of the trifluoroacetic acid. To the residue, 2 ml of triethylamine was added, the mixture was stirred at room temperature, 0.19 g of WSC, 0.14 g HOBt and 41 mg of N, N-dimethylglycine were added and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, the resulting crystals were filtered off, washed with ethanol, and then dried to obtain 16 mg of N- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanyl-methyl] pyridin-2 ylmethyl} -2-dimetyloaminoacetamidu.

The whole product was dissolved in 2 mL of ethanol, 1 mL of 1 mol / L hydrochloric acid in ethanol was added to the solution, and then the ethanol was removed under reduced pressure to give the desired compound as the hydrochloride salt as a white powder.

¹H-NMR (DMSO-d₆) δ: 10.24 (1H, s), 8.36 (1H, t, J = 6.0 Hz), 8.25-7.65 (2H, broad 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). Example 32

To 0.3 g of the compound of Example 30 was added 2 ml of trifluoroacetic acid and the mixture was stirred at room temperature for 1 hour. Trifluoroacetic acid was then removed from the reaction mixture under reduced pressure, and the residue was dissolved in 2 mL of acetonitrile. To the resulting solution, 4 mL of 28% aqueous ammonia was added and the resulting crystals were filtered to obtain 0.2 g of N- {4- [6 amino-2- (6-aminomethylpyridin-2-ylmethylsulfanyl) -5-cyanopyrimidin-4-yl] phenyl} acetamide in the form of a white powder.

¹H-NMR (DMSO-d₆) δ: 10.25 (1H, s), 8.25-7.65 (2H, wide 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).

130

Example 33

The compound of Example 32 (0.2 g) and triethylamine (0.5 mL) were dissolved in 2 mL of DMF. To the solution, 0.1 g of 4-pyrrolidin-1-ylbutanoic acid hydrochloride, 0.07 g of HOBt and 0.1 g of WSC were added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the resulting crystals were filtered off. The crude crystals were crystallized from ethanol to give 43 mg of N- {6- [4- (4-acetylaminophenyl) 6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-ylmethyl} -4-pyrrolidin-1-ylbutylamide.

The whole product was dissolved in 2 mL of ethanol, 1 mL of 1 mol / L hydrochloric acid in ethanol was added to the solution, and then the ethanol was removed under reduced pressure to give the hydrochloride of the desired compound as a white powder.

<td></td><td>¹H-NMR</td><td colspan="2">(DMSO-d₆) δ: 10.24 (1H,</td><td>s), 8.40</td><td>(1H,</td><td>t</td><td>J</td><td> = 6,0</td>

<td>Hz),</td><td> 8,25-7,</td><td>65 (2H,</td><td>broad s), 7.85</td><td>(1H, d, J</td><td colspan="2">= 8.7 Hz</td><td> ),</td><td> 7,74-</td>

<td> 7,66</td><td>(3H, m)</td><td> , 7,41</td><td>(1H, d, J = 7.5</td><td>Hz), 7.12</td><td>(1H,</td><td>d</td><td>J</td><td> = 7,5</td>

<td>Hz),</td><td> 4,47 (</td><td>2H, s),</td><td>4.31 (2H, d, J</td><td>= 6.0 Hz),</td><td colspan="2"> 2,32-2,</td><td> 38</td><td>(6H,</td>

m), 2.20 (2H, t, J = 7.2 Hz), 2.09 (3H, s), 1.75-1.57 (6H, m). Example 34 t-butyl {6-hydroxymethylpyridin-2-ylmethyl) methylcarbamate (0.76 g) and diisopropylethylamine (0.78 mL) were added to 10 mL of methylene chloride, 0.23 mL of methanesulfonyl chloride was introduced at room temperature, and the mixture was stirred within 1 hour. Water was added to the reaction mixture, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resulting oil was dissolved in 20 ml of ethanol, 0.23 g of thiourea was added and the mixture was heated to reflux for 1 hour. After allowing the reaction mixture to cool, the solvent was removed under reduced pressure, and the residue was washed with diethyl ether

131 obtaining 0.9 g of light brown oil. All product and 0.63 g N- [4- (2,2-dicyanovinyl) phenyl] acetamide was dissolved in 20 mL of ethanol and the solution was heated to reflux for 2 hours. 0.32 g NBS was added to the reaction mixture, and the mixture was heated to reflux for an additional 5 minutes. After allowing the reaction mixture to cool, the solvent was removed under reduced pressure. The residue was dissolved in chloroform, washed with water (twice) and brine (once), and then dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, the resulting oil was purified by silica gel chromatography (methylene chloride - methanol - aqueous ammonia = 90: 10: 1). The obtained crude crystals were crystallized from ethyl acetate-hexane to obtain 0.51 g of {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl} pyridin-2-ylmethyl} methyl carbamate t- butyl in the form of white powder. ¹H-NMR (DMSO-d₆) δ: 10.24 (1H, s), 7.84 (2H, d, J = 8.4 Hz),

<td>7.75-7.69 (3H, m),</td><td> 7,43</td><td>(1H, d, J = 7.5 Hz),</td><td>7.05 (1H,</td><td>d</td><td>J =</td>

<td>7.5 Hz), 4.48 (3H,</td><td>s), 4,</td><td>43 (2H, s), 2.85 (3H</td><td>, s) 2.09 (</td><td>3H,</td><td>s),</td>

<td>1.51-1.25 (9H, m).</td><td></td><td></td><td></td><td></td><td></td>

<td>Example 35</td><td></td><td></td><td></td><td></td><td></td>

<td>According to such</td><td>same</td><td>procedure described</td><td colspan="2">in the example</td><td> 32,</td>

using the compound of Example 34 instead of the compound of Example as starting material, N- {4- [6-amino-5-cyano-2- (6-methylaminomethylpyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide was obtained as a white powder .

¹H-NMR (DMSO-d₆) δ: 10.24 (1H, s), 7.65-8.25 (2H, broad s), 7.84 (2H, d, J = 8.7 Hz), 1.12-1.66 ( 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).

132

Example 36

Following the same procedure described in Example 33, using the compound of Example 35 instead of the compound of Example 32, N- {6- [4- (4-acetylaminophenyl) -6amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-methylmethyl- lo} -N-methyl-4-pyrrolidin-1-ylbutylamide as a white powder.

¹H-NMR (DMSO-d₆) δ: 10.23 (1H, s), 8.22-7.66 (2H, broad

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).

Example 37

The compound of Example 32 (0.5 g) and triethylamine (0.3 ml) were dissolved in 5 ml of DMSO, 0.17 g of 3-bromopropionyl chloride was added to the solution at ice temperature, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with chloroform, washed with water (twice) and brine (once), and then the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed and the obtained crude crystals were washed with diethyl ether to give 0.12 g of N- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanyl-methyl] pyridin-2-methyl} acrylamide in white powder forms.

<td>¹H-NMR (DMSO-d₆)</td><td>δ: 10.29 (1H, s), 8.73-8,</td><td> 65</td><td>(1H, m)</td><td> , 8</td><td> ,25-</td>

<td>7.65 (2H, wide s)</td><td>, 7.84 (2H, d, J = 9 Hz)</td><td> , 7</td><td> ,81-7,</td><td> 70</td><td>(3H,</td>

<td>m), 7.50-7., 45 (1H,</td><td>m), 7.23-7.11 (1H, m), 6</td><td> ,20-</td><td> 5,79 (</td><td>3H,</td><td>m),</td>

<td>4.51-4.32 (4H, m), 2,</td><td>10 (3H, s).</td><td></td><td></td><td></td><td></td>

<td>Example 38</td><td></td><td></td><td></td><td></td><td></td>

<td>Relationship with</td><td>Example 37 (0.11</td><td></td><td>g)</td><td>and</td><td> 4-</td>

<td>piperidinopiperidine</td><td>(0.1 g) dissolved</td><td>in</td><td>2 ml</td><td>DMS</td><td>O and</td>

the solution was stirred at room temperature overnight. Down

133 reaction solution, chloroform and water were added, the organic layer was washed with water (twice), then with brine (once), and the organic layer was dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel chromatography (methylene chloride - methanol - 28% aqueous ammonia = 90: 10: 1) to give 50 mg of N- {6- [4- (4- acetylaminophenyl) -6amino -5-cyano-pyrimidin-2-ylsulfanyl-methyl] pyridin-2-ylmethyl} -3- [1,4 '] bipiperidinyl-1'-yl--pionamidu. This product was converted to the hydrochloride form (slightly yellow oil) according to the procedure in Example 31.

¹H-NMR (DMSO-d₆) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.7 Hz),

<td> 7,</td><td> 71</td><td>(2H,</td><td>d, J.</td><td>= 8.7 Hz),</td><td> 7,66</td><td>(1H,</td><td>t, J.</td><td> = 7,2</td><td>Hz), 7.33 (1H,</td>

<td>d</td><td>J</td><td> = 7,</td><td>2 Hz)</td><td>, 7.15 (1H,</td><td>d, J.</td><td> = 7,</td><td>2 Hz)</td><td> , 4,46</td><td>(2H, s), 3.55-</td>

<td> 3,</td><td> 52</td><td>(4H,</td><td>m),</td><td>2.86 (2H, vol</td><td>, J =</td><td> 7,2</td><td>Hz),</td><td> 2,60 (</td><td>2H, t, J = 7.2</td>

<td>h</td><td> ),</td><td> 2,39</td><td>(4H,</td><td>wide t),</td><td> 2,03 (</td><td>3H,</td><td>s).</td><td></td><td></td>

Example 39

To 0.2 g of the compound of Example 30 was added 1 ml of trifluoroacetic acid, the mixture was stirred at room temperature for 30 minutes, and then the reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in 5 ml of acetonitrile, 2 ml of triethylamine was added to the solution, and the mixture was stirred at room temperature. Then 63 mg of 4-methylpiperazine-1-carbonyl chloride hydrochloride salt was added and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the resulting crystals were filtered off, washed with ethanol, and then dried to obtain 35 mg of {4- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-ylmethyl} amide 4 methyl-piperazine-1-carboxylic acid isopropyl ester. This product was converted to the hydrochloride form (white powder) according to the procedure in Example 31.

134 ¹H-NMR (DMSO-d₆) δ: 10.24 (1H, s), 8.25-7.65 (2H,

<td colspan="2">wide</td><td>s),</td><td> 7,86</td><td>(2H,</td><td>d, J = 8.7</td><td>Hz), 7.74-7.65 (3H,</td><td>m), 7.38</td>

<td>(1H,</td><td>d</td><td>J =</td><td colspan="2">7.5 Hz),</td><td> 7,17-7,10</td><td>(2H, m), 4.47 (2H,</td><td>s), 4.31</td>

<td>(2H,</td><td>d</td><td>J =</td><td> 6,0</td><td>Hz),</td><td> 3,35-3,30</td><td>(4H, m), 2.31-2.24</td><td>(4H, m),</td>

<td> 2,37(</td><td>3H,</td><td>s),</td><td> 2,10</td><td>(3H,</td><td>s).</td><td></td><td></td>

<td colspan="2">Example</td><td> 40</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Down</td><td colspan="2">suspension</td><td> 0,1</td><td>compound</td><td>from Example 32 in 5</td><td>ml DMSO,</td>

0.25 ml of diisopropylethylamine was added and 0.04 ml of 1-propane sulfonyl chloride was added dropwise with stirring. After 30 minutes, water was added to the reaction mixture, the resulting crystals were filtered off and dried under reduced pressure to obtain 80 mg of N- [4- (6-amino-5-cyano-2- {6 - [(propane-1-sulfonylamino) methyl ] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide as a white powder.

¹H-NMR (DMSO-d₆) 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).

Example 41

To a suspension of 0.1 g of the compound of Example 35 in 5 ml of acetonitrile was added 0.25 ml of diisopropylethylamine and 0.04 ml of 1-propanesulfonyl chloride was added dropwise with stirring. After 1 hour, water was added to the reaction mixture, the resulting crystals were filtered off and dried under reduced pressure to obtain 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 in the form of a white powder.

<td>¹H-NMR (DMSO-d₆) δ: 10.23 (</td><td>1H,</td><td>s), 7.65-8.20</td><td>(5H,</td><td>m), 7.49</td>

<td>(1H, df J = 7.8 Hz), 7.27 (1H,</td><td>d</td><td>J = 7.8 Hz),</td><td> 4,50</td><td>(2H, s),</td>

<td>4.40 (2H, s), 2.77-3.32 (2H, m)</td><td>^,</td><td>2.79 (3H, s),</td><td> 2,09</td><td>(3H, s),</td>

<td>1.61-1.76 (3H, m), 0.96 (3H, t, J</td><td> =</td><td>7.2 Hz).</td><td></td><td></td>

135

Structures of each of the compounds obtained

Examples 30-41 are shown in Table 5 below.

Table 5 according to

N

<img file="PL1740574T3_D0096.tif" />

S

N R3

<td>Example No.</td><td>R³ =</td>

<td> 30</td><td>ABOUT AND N OtBu H</td>

<td> 31</td><td>Oh me H</td>

<td> 32</td><td></td>

<td> 33</td><td>H</td>

<td> 34</td><td>ABOUT AND N OtBu Me</td>

136

<td> 35</td><td>JME N H</td>

<td> 36</td><td>Me</td>

<td> 37</td><td>ABOUT H</td>

<td> 38</td><td>ABOUT NN^HN AT</td>

<td> 39</td><td>ABOUT^HMe</td>

<td> 40</td><td>0. / 0 V ^^ N ^ ^Xn-pr H</td>

<td> 41</td><td>0. / 0 S '' '^' N '' ' ^Χη.-Ρ ' Me</td>

Example 42

Thiourea (5.33 g) was dissolved in 70 ml of ethanol at 60 ° C, 19.21 g of compound was added to the solution

Reference Example 10 in 50 ml 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. In addition, 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 brine, dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue was dissolved in 200 ml of ethanol and 2 g of NBS was added every 1 hour at reflux temperature, four times in total. After cooling, the reaction mixture was poured into a saturated aqueous solution, extracted with ethyl acetate. The brine layer, dried over anhydrous concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (chloroform - methanol = 10: 1) and crystallized with acetone - IPE to give 16.19 g of 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2 t-butyl-yl-sulfanylmethyl] pyridin-2-yl} propionate as a slightly yellow powder.

sodium bicarbonate and organic was washed with magnesium sulfate and ¹H-NMR (DMSO-d₆) 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). Example 43

Compound of Reference Example II (3 g) was dissolved in 50 mL of dichloromethane, 4 mL of diisopropylethylamine was added, 1.3 mL of methanesulfonyl chloride was added dropwise at ice temperature, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Gained

138 the brown oil was dissolved in 50 ml of ethanol, 1.0 g of thiourea was added and the mixture was heated to reflux for 1 hour. After allowing to cool, 2.5 g of N- [4- (2,2-dicyanovinyl) phenyl] acetamide, 5 mL of diisopropylethylamine and one drop of DBU were added to the reaction solution, and the mixture was stirred at room temperature overnight. After completion of the reaction, the solvent was removed under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, 1.8 g of NBS was added under ice-stirring, and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, the organic layer was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The resulting white oil was crystallized from 2-propanol and then recrystallized from 2-propanol to give 2.3 g of 3- {6 [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2- ethyl} propionate as a white powder.

<td></td><td>¹H-NMR (DMSO-d₆) δ:</td><td> 10,</td><td>23 (1H, s),</td><td> 7,26-8</td><td> ,20</td><td>(2H,</td>

<td colspan="2">wide s) 7.83 (2H, d,</td><td>J = 8</td><td>, 7 Hz), 7.72</td><td>(2H, d,</td><td>J =</td><td> 8,7</td>

<td>Hz),</td><td>7.63 (IH, t, J = 7.8</td><td>Hz),</td><td>7.35 (1H, d,</td><td>J = 7.8</td><td>Hz)</td><td> 7,15</td>

<td>(1H,</td><td>d, J = 7.8 Hz) 4.45</td><td>(2H,</td><td>s), 4.03 (2H,</td><td>q, J =</td><td> 7,2</td><td>Hz),</td>

<td> 2,98</td><td>(2H, t, J = 7.2 Hz),</td><td> 2,70</td><td>(2H, t, J = 7</td><td>, 2 Hz),</td><td> 2,09</td><td>(3H,</td>

s), 1.14 (3H, t, J = 7.2 Hz).

Example 44

According to the procedure described in Example 43, using the compound of Reference Example 12 instead of the compound of Reference Example 11, thiourea and N- [4- (2,2-dicyanovinyl) phenyl] acetamide, 3- {6- [4- (4- methyl acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} propionate in the form of a white powder.

¹H-NMR (DMSO-d₆) δ: 10.23 (1H, s), 8.20-7.60 (2H, wide s), 7.83 (2H, d, J = 8.7Hz), 7.72 (2H, d, J = 8.7

139

Hz), 7.63 (1H, t, J = 7.8, 7.8 Hz), 7.35 (1H, d, J = 7.8 Hz),

3.15 (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).

Example 45

The compound of Example 42 (8.21 g) was cooled to ice temperature, 30 ml TFA was added and the mixture was stirred at room temperature for 1.5 hours. TFA was removed under reduced pressure, then 100 mL of chloroform was added to the residue and evaporated again under reduced pressure. The residue was dissolved in acetone, 18 ml of 1N hydrochloric acid were added, and the mixture was concentrated to dryness 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] pyridin-2-yl} propionic acid hydrochloride as slightly yellow powder.

<td></td><td>¹H-NMR (CD₃OD) δ: 8.38</td><td>(1H,</td><td>t, J.</td><td> = 7,</td><td> 8</td><td>Hz)</td><td>, 8.05 (1H,</td><td>d</td><td>J</td>

<td> = 7,</td><td>8 Hz), 7.82 (2H, d, J =</td><td> 9,0</td><td>Hz),</td><td> 7,81</td><td> (</td><td>1H,</td><td>d, J = 7.8</td><td>Hz)</td><td>^,</td>

<td> 7,72</td><td>(2H, d, J = 9.0 Hz),</td><td> 4,69</td><td>(2H,</td><td>s),</td><td> 3</td><td> ,15</td><td>(2H, t, J =</td><td> 6,</td><td> 9</td>

Hz), 2.84 (2H, t, J = 6.9 Hz), 2.16 (3H, s).

Example 46

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

140

The compound (69 mg) was dissolved in methanol, 0.29 mL of 1N hydrochloric acid was added, and the mixture was concentrated to dryness under reduced pressure. The residue was crystallized from methanol-IPE to give 67 mg of the hydrochloride of the above compound (slightly yellow powder).

The characteristics of this hydrochloride salt are shown below:

¹H-NMR (CD₃OD) 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).

Example 47

Following the same procedure described in Example 42, using the compound of Reference Example 14 instead of the compound of Reference Example 10, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] -pyridine- 2-yl} t-butyl acrylate as a light brown powder.

<td>¹H-NMR</td><td>(DMSO-d₆)</td><td>δ: 10.22</td><td>(1H,</td><td>s), 7.82</td><td>(2H, d,</td><td>J =</td><td> 8,7</td>

<td>Hz), 7.79 (</td><td>1H, t, J =</td><td>7.5 Hz),</td><td> 7,70</td><td>(2H, d,</td><td>J = 8.7</td><td>Hz),</td><td> 7,60</td>

<td>(1H, d, J =</td><td>7.5 Hz),</td><td>7.55 (1H,</td><td>d, J.</td><td colspan="2">= 7.5 Hz), 7.53</td><td>(1H,</td><td>d, J.</td>

<td>= 15.9 Hz),</td><td>6.78 (1H,</td><td>d, J = 15</td><td>, 9 Hz</td><td> ), 4,53 (</td><td>2H, s),</td><td> 2,08</td><td>(3H,</td>

s), 1.48 (9H, s).

Example 48

Into a round-bottomed flask, 251 mg of the compound of Example 47 was introduced. After the flask had cooled to ice temperature, 0.5 mL of TFA was also added, and the mixture was stirred at room temperature for 1 hour. After removing the TFA under reduced pressure, 5 mL of acetonitrile was added to the oily residue, and 5 mL of triethylamine was added dropwise with stirring. Then 50 mg of N-methylpiperazine and 455 mg of BOP reagent were added, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure

141 pressure, purified by silica gel chromatography (chloroform - methanol - aqueous ammonia = 200: 10: 1) to obtain 40 mg of N- [4- (6-amino-5-cyano-2- {6- [3- ( 4metylopipe pyrazin-1-yl) -3-oxo-propenyl] -pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide. The whole product was dissolved in ethanol, 0.15 mL of 1 mol / L hydrochloric acid in ethanol was added to the above solution, and then the solvent was removed to obtain 48 mg of the above compound as the hydrochloride (white powder).

The characteristics of this hydrochloride salt are as follows:

<td></td><td>¹H-NMR</td><td>(DMSO-d₆) δ: 10.2 (</td><td>1H, s), 7</td><td> ,82</td><td>(2H, d, J = 9.0</td>

<td>Hz),</td><td> 7,76 (</td><td>1H, d, J = 7.8 Hz),</td><td>7.70 (2H,</td><td>d, J.</td><td>= 9.0 Hz), 7.61</td>

<td>(1H,</td><td>d, J =</td><td>7.8 Hz), 7.51 (1H,</td><td>d, J = 7,</td><td>8 Hz)</td><td>, 7.46 (2H, s),</td>

<td> 4,53</td><td>(2H, p</td><td>), 3.57 (4H, wide</td><td>t), 2.31</td><td>(4H,</td><td>broad t), 2.19</td>

(3H, s), 2.08 (3H, s).

Example 49

Following the same procedure described in Example 43, using the compound of Reference Example 13 instead of the compound of Reference Example 11, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2 was obtained Ethyl-yl} -2-methylpropionate as a slightly yellow powder.

¹H-NMR (CDCl₃) 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, wide 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). Example 50

The compound of Example 49 (1.13 g) was dissolved in 30 mL of ethanol, 7.5 mL of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight.

142

The solvent was removed under reduced pressure, the residue was neutralized with a 2% aqueous citric acid solution and dispersed, and then insoluble was filtered off. The obtained crude product was purified by silica gel chromatography (methylene chloride - methanol = 10: 1) to obtain 597 mg of 3- {6- [4- (4-acetylaminophenyl) 6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridinium acid 2-yl} 2-methylpropionic as a colorless powder.

¹H-NMR (DMSO-d₆) 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, 1.2 (1H, d, J = 7.5 Hz), 4.47 (2H, s), 3.05 (1H, dd, J = 13.8, 6.9 Hz), 2.86 (1H , sextet, 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).

Example 51

Following the same procedure described in Example 46, using the compound of Example 50 instead of the compound of Example 45, 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 as a slightly yellow powder.

¹H-NMR (DMSO-d₆) 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).

Example 52

To 9 ml of dichloromethane, the compound of Reference Example 15 (540 mg) and diisopropylethylamine (244 mg) was added. After the mixture was stirred at ice temperature for 10 minutes, 0.16 ml of methanesulfonyl chloride was added dropwise to the mixture, and then the mixture was stirred at room temperature for 1 hour. The resulting mesylate solution was added dropwise to

143 a solution of 142 mg of thiourea in 2 ml of ethanol at 60 ° C and the mixture was stirred at the same temperature for 1 hour. After removing the solvent from the reaction mixture, 9 ml of ethanol, 396 mg of N- [4- (2,2-dicyanovinyl) phenyl] acetamide and 473 mg of sodium bicarbonate were added to the residue, and the mixture was heated to reflux for 2 hours. After allowing to cool, 270 mg of NBS was added to the reaction mixture, and the mixture was heated to reflux for 30 minutes, then the solvent was removed under reduced pressure, and a saturated aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with chloroform, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine = 600: 20: 1), then crystallized 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 as a white powder.

¹H-NMR (DMSO-d₆) 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), 2.292.21 (4H, m), 2.14 ( 3H, s), 2.09 (3H, s).

Example 53

To 7 mL of ethanol, the compound of Example 16 (2.28 g) and thiourea (545 mg) were added, followed by stirring at 60 ° C for 1.5 hours. After allowing the mixture to cool, 1.40 g of N [4- (2,2-dicyanovinyl) phenyl] acetamide and 1.46 g of triethylamine were added thereto, and the mixture was stirred at 60 ° C for 4 hours. The resulting reaction solution was cooled to ice temperature, 827 mg of NBS was added, and the mixture was stirred in the same

144 temperature within 30 minutes. The solvent was removed 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 brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride ethanol = 30: 1} to give 1.86 g of 5- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridine- T-butyl 2-yl} pentanoate as a white powder.

¹H-NMR (DMSO-d₆) δ: 10.2 (1H, s), 7.83 (2H, d, J = 8.4

<td>Hz),</td><td> 7,70</td><td>(2H,</td><td>d, J =</td><td> 8,4</td><td>Hz),</td><td>7.62 (1H,</td><td>t</td><td>J = 7.5</td><td>Hz), 7.34</td>

<td>(1H,</td><td>d, J.</td><td> = 7,</td><td>5 Hz),</td><td> 7,10</td><td>(1H,</td><td>d, J = 7,</td><td> 5</td><td>Hz), 4.45</td><td>(2H, s),</td>

<td> 2,69</td><td>(2H,</td><td>t, J.</td><td> = 7,5</td><td>Hz),</td><td> 2,19</td><td>(2H, t, J</td><td> =</td><td>7.5 Hz),</td><td>2.08 (3H,</td>

<td>s), 1</td><td> ,66-1</td><td> ,47 (</td><td>4H, m),</td><td> 1,37</td><td>(9H,</td><td>s).</td><td></td><td></td><td></td>

Example 54

The compound of Example 53 (1.06 g) was cooled to ice temperature, 2 mL of TFA was added dropwise and the mixture was stirred at room temperature for 1.5 hours. The remaining TFA was removed under reduced pressure, the residue was dissolved in 20 ml DMF. The solution was neutralized with 3 ml of triethylamine at ice temperature and after adding a further 1.8 g of HOBt, it was stirred for 15 minutes. To the reaction mixture, 200 mg of N-methylpiperazine and 764 mg of WSC were added, followed by stirring at room temperature overnight. The resulting reaction mixture was evaporated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was removed. The residue was purified by silica gel chromatography (methylene chloride - methanol - triethylamine = 300: 10: 1) to obtain 1.0 g N- [4145 (6-amino-5-cyano-2- {6- [5- (4- methylpiperazin-1-yl) -5-oxopentyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide as a white powder.

¹H-NMR (CDCl₃) δ: 8.34 (1H, s), 7.90 (2H, d, J = 8.4 Hz),

<td> 7,67</td><td>(2H,</td><td>d, J = 8</td><td>, 4 Hz),</td><td> 7,52</td><td>(1H, t,</td><td>J = 7.5</td><td>Hz), 7,</td><td> 31</td><td>(1H, d,</td>

<td>J =</td><td> 7,5</td><td>Hz), 7.01</td><td>(1H, d,</td><td>J =</td><td>7.5 Hz)</td><td> , 5,71</td><td>(2H, s),</td><td> 4,</td><td>50 (2H,</td>

<td>s),</td><td> 3,62</td><td>(2H, t,</td><td>J = 5.1</td><td>Hz),</td><td> 3,50 (</td><td>2H, t,</td><td>J = 5.1</td><td>h</td><td> ), 2,82</td>

<td>(2H,</td><td>t</td><td>J = 7.5</td><td>Hz), 2,</td><td> 44-2,</td><td>34 (6H,</td><td>m), 2,</td><td>30 (3H,</td><td>s)</td><td> , 2,20</td>

<td>(3H,</td><td>s),</td><td> 1,86-1,73</td><td>(4H, m).</td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 55

Following the same procedure described in Example 54, using 1- (2-diethylaminoethyl) piperazine instead of N-methylpiperazine, N- {4- [6-amino-5-cyano-2- hydrochloride (6 {5- [4- ( 2-diethylaminoethyl) piperazin-1-yl] -5-oxopentyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide as a white powder.

¹H-NMR (DMSO-d₆) 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).

Example 56

The compound of Example 46 (1 g) was suspended in a mixed solvent of 10 mL ethanol and 10 mL water. To the suspension, 10 mL of 5N hydrochloric acid was added, and the mixture was stirred for 4 hours by heating at 60 ° C. After removing ethanol under pressure, under reduced 5N aqueous solution

The resulting crystals of the reaction mixture, the mixture was neutralized with sodium hydroxide at ice temperature, filtered, washed with diethyl ether, and then dried under reduced pressure to obtain 0.85 g of 4 amino-6- (4- amophenyl) -2- {6- [3 - (4-methyl-piperazin-1-yl) -3146 oxopropyl] pyridin-2-ylmethylsulfanyl} -pyrimidin-5-carbonitrile in the form of a white powder.

¹H-NMR (DMSO-d₆) δ: 7.73 (2H, d, J = 8.7 Hz), 7.80-7.55 (2H, broad s), 7.6.1 (1H, t, J = 7.8 Hz) , 7.33 (IH, 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).

Example 57

The compound of Example 56 (150 mg) and triethylamine (0.5 mL) were dissolved in 10 mL of acetonitrile, 0.1 g of propionyl chloride was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. After removal of the solvent, the residue was dissolved in chloroform. Then water was added, the organic layer was washed with water (twice), brine (once) and dried over magnesium sulfate. After removal of the solvent under reduced pressure, the obtained oil was purified by silica gel chromatography (methylene chloride - methanol - aqueous ammonia = 90: 10: 1) to obtain 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 as a slightly yellow powder.

<td></td><td>¹H-NM</td><td>R (DMSO-d₆) δ:</td><td> 10,</td><td>16 (1H, s),</td><td> 8,20-7,64</td><td>(2H,</td>

<td>W</td><td>oki s)</td><td>, 7.84 (2H, d, J</td><td> =</td><td>8.7 Hz), 7.74</td><td>(2H, d, J =</td><td> 8,7</td>

<td>Hz),</td><td> 7,62</td><td>(1H, t, J = 7.8 Hz</td><td> ),</td><td>7.34 (1H, d,</td><td>J = 7.8 Hz)</td><td> 7,14</td>

<td>(1H,</td><td>d, J.</td><td>= 7.8 Hz), 4.46</td><td>(2H</td><td>, s), 3.42-3,</td><td>35 (4H, m),</td><td> 2,94</td>

<td>(2H,</td><td>t, J.</td><td colspan="2">= 7.2 Hz), 2.70 (2H,</td><td>t, J = 7.2 Hz</td><td>), 2.37 (2H,</td><td>q, J</td>

<td> = 7,</td><td>5 Hz),</td><td>2.20-2.16 (4H, m),</td><td> 2,</td><td>12 (3H, s), 1,</td><td>10 (3H, t, J</td><td> = 7,5</td>

Hz).

147

Example 58

Following the same procedure described in Example 57, using butyryl chloride instead of propionyl chloride, N- [4- (6-amino-5-cyano-2- {6- [3- (4-methylpiperazin-1-yl) -3-oxopropyl was obtained ] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] butylamide as a white powder.

¹H-NMR (DMSO-d₆) 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),

<td colspan="2">3.40-3.35 (4H, m),</td><td> 2,94</td><td>(2H, t, J = 7.5 Hz), 2.70 (2H, t,</td><td>J =</td>

<td>7.5 Hz),</td><td> 2,20-2,16</td><td>(4H,</td><td>m), 2.12 (3H, s), 1.63 (2H, sect,</td><td>J =</td>

<td>7.5 Hz),</td><td>0.93 (3H,</td><td>t, J =</td><td>7.5 Hz).</td><td></td>

<td>Example</td><td> 59</td><td></td><td></td><td></td>

<td colspan="2">According to such</td><td>same</td><td>procedure described in the Example</td><td> 46,</td>

using N- (tert-butoxycarbonyl) ethylenediamine instead of N-methylpiperazine, [2- (3- {6- [4- (4-acetylaminophenyl) 6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} propionylamino) was obtained ethyl] t-butyl carbamate as a colorless powder.

¹H-NMR (DMSO-d₆) δ: 10.24 (1H, s), 7.88 (1H, broad t, J =

<td> 7,</td><td>5 Hz</td><td> ),</td><td>7.83 (2H, d, J</td><td>= 8.4 Hz),</td><td> 7,72</td><td>(2H,</td><td>d, J =</td><td> 8,4</td><td>Hz),</td>

<td> 7,</td><td> 62 (</td><td>1H,</td><td>t, J = 7.5 Hz)</td><td>, 7.35 (1H,</td><td>d, J.</td><td> = 7,</td><td>5 Hz),</td><td> 7,12</td><td>(1H,</td>

<td>d</td><td>J</td><td> = 7</td><td>, 5 Hz), 6.77 (</td><td>1H, wide</td><td>t, J.</td><td> = 7,</td><td>5 Hz),</td><td> 4,46</td><td>(2H,</td>

<td>s)</td><td> , 3,</td><td> 05</td><td>(2H, q, J = 7.5</td><td>Hz), 2.98-2</td><td> ,90 (</td><td>4H, m</td><td> ), 2,46</td><td>(2H,</td><td>t, J.</td>

= 7.5 Hz), 2.09 (3H, s).

Example 60

To 100 mg of the compound of Example 59 at ice temperature, 1 ml of TFA was added and the mixture was stirred for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure and dissolved in 10 ml of ethanol. To the solution, 0.37 mL of 1N hydrochloric acid was added, and the mixture was concentrated to dryness under reduced pressure. Obtained solid product

148 crystallized from methanol-IPE to give 90 mg of 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanyl-methyl] pyridin-2-yl} -N- hydrochloride (2- aminoethyl} propionamide as a slightly yellow powder.

¹H-NMR (DMSO-d₆) δ: 10.23 (1H, s), 8.12 (1H, broad t, J = 7.5 Hz), 7.85 (2H, wide s), 7.82 (2H, d, J = 8 , 7 Hz), 7.72 (2H, d, J = 8.7 Hz), 7.57 (1H, wide d, J = 7.5 Hz), 7.34 (1H, wide 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). Example 61

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

The compound obtained in the free form above (187 mg) was dissolved in methanol, 0.721 ml of 1N hydrochloric acid was added, and the mixture was evaporated to dryness under reduced pressure. The resulting solid product was crystallized from methanol - acetone - IPE to give 186 mg of the hydrochloride

3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanyl-methyl] pyridin-2-yl} -N- (2-d ± methylaminoethyl) propionamide in light form yellow powder.

The properties of this hydrochloride are shown as follows:

¹H-NMR (CD₃OD) 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 ).

149

Example 62

Following the same procedure described in Example 61, using N, N, N'-trimethylethylenediamine instead of N, N-dimethylethylenediamine, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2 hydrochloride was obtained -ylsulfanylmethyl] pyridin-2-yl} -N- (2-dimethylaminoethyl) -N-methylpropionamide as a slightly yellow powder.

¹H-NMR (CD₃0D) 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).

Example 63

Following the same procedure described in Example 61, using 39 μΐ of 3-dimethylaminopropylamine instead of N, N-dimethylethylenediamine, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-hydrochloride was obtained. -yl} -N- (2-dimethylaminopropyl) propionamide as a slightly yellow powder.

¹H-NMR (CD₃0D) δ: 8.38 (1H, t, J = 7.8 Hz), 8.05 (1H,

<td>d</td><td>J</td><td>= 7.8 Hz),</td><td>7.83 (2H, d, J</td><td>= 9.0 Hz), 7.80 (1H,</td><td>d</td><td>J =</td>

<td> 7,</td><td> 8</td><td>Hz), 7.72 (</td><td>2H, d, J = 9,</td><td>0 Hz), 4.73 (2H, p</td><td> ),</td><td> 3,23</td>

<td> (2</td><td>H</td><td>t, J = 6.9</td><td>Hz), 3.10 (2H,</td><td>t, J = 6.9 Hz), 2,</td><td> 87</td><td>(2H,</td>

<td>t</td><td>J</td><td>= 6.9 Hz),</td><td>2.85 (6H, s),</td><td>2.79 (2H, t, J = 6</td><td> ,9</td><td>Hz),</td>

<td> 2,</td><td> 16</td><td>(3H, s), 1,</td><td>89 (2H, fifth,</td><td>J = 6.9 Hz).</td><td></td><td></td>

Example 64

Following the same procedure described in Example 61, using N, N, N'-trimethyl-1,3-propanediamine instead of N, N-dimethylethylenediamine, 3- {6 [4- (4-acetylaminophenyl) -6- hydrochloride was obtained amino-5-cyanopyrimidin-2-ylsulfanylmethyl] pyridin-2-yl} -N- (2150 dimethylaminopropyl) -N-methylpropionamide as a slightly yellow powder.

¹H-NMR (CD₃OD) 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 (IH, 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).

Example 65

Following the same procedure described in Example 46, using 1- (2-aminoethyl) piperidine instead of N-methylpiperazine, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl hydrochloride was obtained ] pyridin-2-yl} -N- (2-methylpiperidin-1-ylyl) propionamide as a slightly yellow powder.

¹H-NMR (DMSO-d₆) 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).

Example 66

Following the same procedure described in Example 61, using N, N-diethylethylenediamine instead of N, N-dimethylethylenediamine, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidin-2-ylsulfanylmethyl] hydrochloride was obtained. pyridin-2-yl} -N- (2-diethylaminoethyl) propionamide as a slightly yellow powder.

<td></td><td>¹H-NMR (CD₃OD) δ: 8.39</td><td>(1H,</td><td>t, J.</td><td>= 8.1 Hz), 8.06</td><td>(1H,</td><td>d</td><td>J</td>

<td> = 8,</td><td>1 Hz), 7.83 (2H, d, J =</td><td> 9,0</td><td>Hz),</td><td>7.81 (IH, d, J =</td><td> 8,1</td><td>Hz)</td><td>^,</td>

<td> 7,72</td><td>(2H, d, J = 9.0 Hz), 4</td><td> ,73</td><td>(2H,</td><td>s), 3.51 (2H, t,</td><td>J =</td><td> 6,</td><td> 3</td>

<td>Hz),</td><td>3.30-3.19 (8H, m), 2.82</td><td>(2H</td><td>, t,</td><td>J = 6.3 Hz), 2.17</td><td>(3H,</td><td>s)</td><td>^,</td>

<td> 1,29</td><td>(6H, t, J = 9.0 Hz).</td><td></td><td></td><td></td><td></td><td></td><td></td>

151

Example 67

Following the same procedure described in Example 61, using 1-methyl-4- (methylamino) piperidine instead of N, N-dimethylethylenediamine, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidine hydrochloride was prepared. -2-ylsulfanylmethyl] pyridin-2-yl} -N-methyl-N- (1-methylpiperidin-4-yl) propionamide in the form of a slightly yellow powder.

<td>¹H-NMR (CD₃FROM)</td><td>δ:</td><td>8.39 (IH, t, J = 7.8</td><td>Hz), 8.03 (1H,</td><td>d, J = 7.8</td>

<td>Hz), 7.86 (2H, d, J =</td><td> 9,0</td><td>Hz), 7.83 (1H, d,</td><td>J = 7.8 Hz), 7.7</td><td>3 (2H, d,</td>

<td>J = 9.0 Hz), 4.80 (2H,</td><td>s),</td><td>3.64-3.47 (2H, m),</td><td>3.24 (2H, t, J =</td><td>6.3 Hz),</td>

<td>3.17-3.12 (1H, m),</td><td> 2,99</td><td>(2H, t, J = 6.3</td><td>Hz), 2.98-2.89</td><td>(2H, m),</td>

<td>2.91 (3H, s), 2.79 (</td><td>3H,</td><td>s), 2.16 (3H, s),</td><td>2.10-1.76 (4H,</td><td>m).</td>

<td>Example 68</td><td></td><td></td><td></td><td></td>

Following the same procedure described in Example 61, using 4- (diethylamino) piperidine instead of N, N-dimethylethylenediamine, N- [4- (6-amino-5-cyano-2 {6- [3- (4-diethylaminopiperidine) hydrochloride was obtained -1-yl) -3-oxopropyl] pyridin-2-methylsulfanyl} pyrimidin-4-yl) phenyl] acetamide as a colorless powder.

¹H-NMR (CD₃OD) 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, wide d, J = 12.6 Hz), 4.06 (1H, wide d, J = 12.6 Hz), 3 , 64-3.53 (1H, m), 3.332.62 (8H, m), 2.16 (3H, s), 2.16-1.56 (4H, m), 1.35 (6H, t , J =

7.2 Hz).

Example 69

Following the same procedure described in Example 46, using 4-piperidinopiperidine instead of N-methylpiperazine, N- (4- {6-amino-2- [6- (3- [1,4 '] biperiperidinyl-1'-yl hydrochloride was obtained -3-oxopropyl) pyridin-2-ylmethylsulfanyl] -5-cyanopyrimidin-4-yl} phenyl) acetamide as a slightly yellow powder.

152

<td></td><td>¹H-NMR (DMSO-d₆)</td><td>δ: 10.45</td><td>(1H,</td><td>s), 8.27 (IH, t, J =</td><td> 7,5</td>

<td>Hz),</td><td>7.93 (IH, t, J =</td><td>7.5 Hz),</td><td> 7,81</td><td>(2H, d, J = 9.0 Hz),</td><td> 7,76</td>

<td>(2H,</td><td>d, J = 9.0 Hz),</td><td>7.74 (1H,</td><td>d</td><td>J = 7.5 Hz), 4.76 (2H</td><td>, S)</td>

<td> 4,46</td><td>(1H, wide d,</td><td>J = 13.2</td><td>Hz),</td><td>4.00 (1H, broad d,</td><td>J =</td>

<td> 13,2</td><td>Hz), 3.35-3.17 (</td><td>6H, m), 3,</td><td> 05-2</td><td>, 84 (4H, m), 2.56-2.48</td><td>(1H,</td>

m), 2.15-2.07 (2H, m), 2.10 (3H, s), 1.97-1.35 (8H, m).

Example 70

Following the same procedure described in Example 46, using 2-piperidinomethanol instead of N-methylpiperazine, N- [4- (6-amino-5-cyano-2- {6- [3- (2-hydroxymethylpiperidin-1-yl) hydrochloride was obtained ) -3-oxopropyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide in the form of a white powder.

¹H-NMR (DMSO-d₆) δ: 10.24 (1H, s), 8.25-7.50 (2H, broad 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).

Example 71

Following the same procedure described in Example 46, using 2-piperidin-1-ylmethylmorpholine instead of N-methylpiperazine, N- [4- (6-amino-5-cyano-2- {6 [3-oxo-3- ( 2-piperidin-1-ylmethylmorpholin-4-yl) propyl] pyridin-2-ylmethylsulfanyl} pyrimidin-4-yl) phenyl] acetamide as a white powder.

¹H-NMR (DMSO-d₆) 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), 2.482.20 (8H, m), 2.08 (3H, s), 1.42-1.32 (6H, m).

153

Example 72

Following the same procedure described in Example 46, using 2- (4-ethylpiperazin-1-ylmethyl) morpholine instead of N-methylpiperazine, 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 in the form of a white powder.

<td></td><td> 1</td><td>H-NMR (</td><td>DMSO-d₆)</td><td>δ: 10.2</td><td>(1H, s),</td><td> 7,83</td><td>(2H,</td><td>d</td><td>J =</td>

<td> 8,</td><td>4 Hz)</td><td> , 7,71</td><td>(2H, d,</td><td>J = 8.4 Hz</td><td> ), 7,62 (</td><td>1H, vol</td><td>, .J =</td><td> 7,8</td><td>Hz),</td>

<td> 7,</td><td> 34 (</td><td>1H, d,</td><td>J = 7.8</td><td>Hz), 7.16 (</td><td>1H, d, J</td><td> = 7,8</td><td>Hz),</td><td> 4,46</td><td>(2H,</td>

<td>s)</td><td> , 4,</td><td> 25-3,75</td><td>(3H, m),</td><td> 2,94-2,73</td><td>(4H, m),</td><td> 2,48-</td><td> 2,20</td><td>(13H,</td><td>m),</td>

2.08 (3H, s), 0.93 (3H, broad t).

Example 73

Following the same procedure described in Example 61, using 1-tert-butoxycarbonylpiperazine instead of N, N-dimethylethylenediamine, 4- (3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidine- T-butyl 2-ylsulfanyl-methyl] pyridin-2-yl} propionyl) piperazin-1-carboxylate in the form of a white powder.

<td></td><td>¹H-NMR</td><td>(DMSO-d₆)</td><td>δ: 10.23</td><td>(1H,</td><td>s), 7.83</td><td>(2H, d, J = 8.7</td>

<td>Hz),</td><td> 7,71 (</td><td>2H, d, J =</td><td>8.7 Hz),</td><td> 7,62</td><td>(1H, t, J</td><td>= 7.8 Hz), 7.34</td>

<td>(1H,</td><td>d, J.</td><td>= 7.8 Hz),</td><td>7.16 (1H,</td><td>d</td><td>J = 7.8 Hz</td><td>), 4.46 (2H, s),</td>

<td> 3,41-</td><td> 3,38 (</td><td>4H, m), 3</td><td> ,30-3,25 (</td><td>4H,</td><td>m), 2.95</td><td>(2H, t, J = 7.5</td>

<td>Hz),</td><td> 2,73 (</td><td>2H, t, J =</td><td>7.5 Hz), 2</td><td> ,09</td><td>(3H, s), 1,</td><td>39 (9H, s).</td>

Example 74

Following the same procedure described in Example 60, using the compound of Example 73, N- (4 {6-amino-5-cyano-2- [6- (3-oxo-3-piperazin-1-ylpropyl) pyridin2- ylmethylsulfanyl] pyrimidin-4-yl} phenyl) acetamide as a slightly yellow powder.

154 ¹H-NMR (CD₃OD) 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). Example 75

Following the same procedure described in Example 61, using 1- (2-diethylaminoethyl) piperazine instead of N, N-dimethylethylenediamine, 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 as a colorless powder.

<td></td><td>¹H-NMR (CD₃FROM)</td><td>δ: 8.39 (</td><td>1H, t, J</td><td>= 7.8 Hz), 8.05 (1H, d,</td>

<td>J =</td><td>7.8 Hz), 7.86</td><td>(1H, d, J</td><td>= 7.8 Hz)</td><td>, 7.83 (2H, d, J = 9.0</td>

<td>Hz),</td><td>7.73 (2H, d, J</td><td>= 9.0 Hz),</td><td>4.73 (2H,</td><td>s), 3.69-3.07 (20H, m),</td>

<td> 2,17</td><td>(3H, s), 1.38 (</td><td>6H, t, J =</td><td>7.2 Hz).</td><td></td>

Example 76

Following the same procedure described in Example 46, using 1- (2-diisopropylaminoethyl) piperazine instead of N-methylpiperazine, N- {4- [6-amino-5-cyano-2- (6- {3- [4- (2) diisopropylaminoethyl) piperazin-1-yl] -3oxopropyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide as a colorless powder.

<td></td><td>¹H-NMR (DMSO-d₆) δ: 10.23</td><td>(1H, s), 7.65-8.20</td><td>(2H, wide</td><td>s),</td>

<td> 7,84</td><td>(2H, d, J = 8.7 Hz), 7,</td><td>72 (2H, d, J = 8.7</td><td>Hz), 7.62 (</td><td>1H,</td>

<td>t, J.</td><td>= 7.8 Hz), 7.34 (1H, d,</td><td>J = 7.8 Hz), 7.14</td><td>(1H, d, J =</td><td> 7,8</td>

<td>Hz),</td><td>4.47 (2H, s), 3.40-3.29</td><td>(4H, m), 2.97-2.71</td><td>(4H, m), 2,</td><td> 69-</td>

<td> 2,51</td><td>(2H, m), 2.49-2.42 (2H,</td><td>m), 2.30-2.18 (6H</td><td>, m) 2.09 (</td><td>3H,</td>

<td>s), 0</td><td>, 92 (12H, d, J = 6.3 Hz).</td><td></td><td></td><td></td>

<td colspan="2">Example 77</td><td></td><td></td><td></td>

Following the same procedure described in Example 61, using 1- [2- (pyrrolidin-1-yl) ethyl] piperazine instead of N, N-dimethylethylenediamine, N- {4- [6-amino155 hydrochloride was obtained

5-cyano-2- (6- {3-oxo-3- [4- (2-pyrrolidin-1-ylethyl) piperazin-1-yl] propyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] -phenyl} -acetamide in the form of a slightly yellow powder.

¹H-NMR (DMSO-d₆D +₂0) 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, broad s).

Example 78

Following the same procedure 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-ethyl) piperazin-1-yl] -3-oxo-propyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} -acetamide as a slightly yellow powder.

¹H-NMR (CD₃0D) δ: 8.39 (1H, t, J = 8.1 Hz), 8.05 (1H, d,

<td>J =</td><td>8.1 Hz), 7.85</td><td>(1H,</td><td>d, J = 8,</td><td>1 Hz)</td><td> , 7,</td><td>83 (2H,</td><td>d</td><td>J = 8.7 Hz),</td>

<td> 7,72</td><td>(2H, d, J =</td><td> 8,7</td><td>Hz), 4.73</td><td>(2H,</td><td>s),</td><td> 4,00</td><td>(4H,</td><td>wide s),</td>

<td> 3,72</td><td>(4H, wide</td><td>s),</td><td> 3,66-3,27</td><td>(14H,</td><td>m),</td><td> 3,09'</td><td>(2H,</td><td>wide s),</td>

<td> 2,17</td><td>(3H, s).</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Example 79

Following the same procedure described in Example 61, using 1- (N-methylpiperidin-4-ylmethyl) piperazine instead of N, N-dimethylethylenediamine, N- {4- [6 amino-5-cyano-2- (6- {3) hydrochloride was obtained - [4- (2-Diethylaminoethyl) piperazin-1-yl] -3-oxo-propyl} pyridin-2-ylmethylsulfanyl) pyrimidin-4-yl] phenyl} acetamide in the form of a slightly yellow powder.

¹H-NMR (CD₃0D) δ: 8.39 (1H, t, J = 8.1 Hz), 8.03 (1H, d,

J = 8.1 Hz), 7.84 (3H, wide 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).

Example 80

156

Following the same procedure described in Example 61, using 1-methyl homopiperazine instead of N, N-dimethylethylenediamine, 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 as a slightly yellow powder.

<td>¹H-NMR (CD₃OD) δ: 8.38 (1H, t,</td><td>J =</td><td>7.8 Hz</td><td> ), 8,02</td><td>(1H, d, J</td>

<td>= 7.8 Hz), 7.84 (2H, d, J = 9.0</td><td>Hz),</td><td> 7,84</td><td>(1H, d,</td><td>J = 7.8</td>

<td>Hz), 7.72 (2H, d, J = 9.0 Hz), 4.72</td><td>(2H,</td><td>s), 4,</td><td> 03-3,05</td><td>(12H, m),</td>

2.89 (3H, s), 2.23-2.06 (2H, m), 2.16 (3H, s).

Example 81

Following the same procedure described in Example 61, using 1-amino-4-methylpiperazine instead of N, N-dimethyl-ethylenediamine, 3- {6- [4- (4-acetylaminophenyl) -6-amino-5-cyanopyrimidine- 2-ylsulfanylmethyl] pyridin-2-yl} -N- (4-methyl-piperazin-1-yl) propionamide as a slightly yellow powder.

¹H-NMR (CD₃OD) 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).

Example 82

Following the same procedure described in Example 43, using the compound of Reference Example 17 instead of the compound of Reference Example 11, N- (4- {6-amino-5-cyano-2- [6- (3-oxopentyl) pyridin-2-ylmethylsulfanyl) was obtained ] pyrimidin-4-yl} phenyl) acetamide as a colorless powder.

¹H-NMR (DMSO-d₆) δ: 10.23

Hz), 7.72 (2H, d, J = 9.0 Hz), (1H, d, J = 7.5 Hz), 7.13 (1H,

2.93 (2H, t, J = 6.9 Hz), 2.81 q, J = 7.2 Hz), 2.09 (3H, s), 0,

<td>(1H,</td><td>s), 7.83 (2H, d, J =</td><td> 9,0</td>

<td> 7,61</td><td>(1H, t, J = 7.5 Hz),</td><td> 7,33</td>

<td>d, J.</td><td>= 7.5 Hz), 4.45 (2H,</td><td>s),</td>

<td>(2H,</td><td>t, J = 6.9 Hz), 2.46</td><td>(2H,</td>

(3H, t, J = 7.2 Hz).

157

Structures of each compound obtained according to the Examples

42-82 are shown in Table 6 below.

Table 6

NHR¹

N

<img file="PL1740574T3_D0097.tif" />

ABOUT

QT

Q is R⁴, R⁶ or R⁷and T means Z³ or R⁸.

<td>Example No.</td><td>R¹</td><td>Q</td><td>T</td>

<td> 42</td><td>ac</td><td>CH2CH2-</td><td>-O-tBu</td>

<td> 43</td><td>ac</td><td>CH2CH2-</td><td>-och₂ch₃</td>

<td> 44</td><td>ac</td><td>CH2CH2-</td><td>-OCH3</td>

<td> 45</td><td>ac</td><td>CH2CH2-</td><td>OH</td>

<td> 46</td><td>ac</td><td>CH2CH2-</td><td>-N \ -Me \ /</td>

<td> 47</td><td>ac</td><td>-CH = CH-</td><td>-O-tBu</td>

<td> 48</td><td>ac</td><td>-CH = CH-</td><td>-N Me</td>

<td> 49</td><td>ac</td><td>CH₂CH (CH₃)-</td><td>-och₂ch₃</td>

<td> 50</td><td>ac</td><td>CH₂CH (CH₃}-</td><td>OH</td>

158

<td> 51</td><td>ac</td><td>CH₂CH (CH₃)-</td><td>-N \ -Me IN</td>

<td> 52</td><td>ac</td><td>-C c-CH₂CH₂-</td><td>-N \ -Me IN</td>

<td> 53</td><td>ac</td><td>- (CH2) 4-</td><td>-O-tBu</td>

<td> 54</td><td>ac</td><td>- (CH2) 4-</td><td>-N \ -Me</td>

<td> 55</td><td>ac</td><td>- (CH2) 4-</td><td>NN Et \ / \ N et</td>

<td> 56</td><td>H</td><td>CH2CH2-</td><td>-N Me</td>

<td> 57</td><td>-CO-Et</td><td>CH2CH2-</td><td>-N \ -Me</td>

<td> 58</td><td>-CO-n-Pr</td><td>CH2CH2-</td><td>-N \ -Me</td>

<td> 59</td><td>ac</td><td>CH2CH2-</td><td>H N O-tBu • T</td>

<td> 60</td><td>ac</td><td>CH2CH2-</td><td>\ AL H</td>

<td> 61</td><td>ac</td><td>CH2CH2-</td><td>Me N Me H</td>

<td> 62</td><td>ac</td><td>CH2CH2-</td><td>Me N Me Me</td>

159

<td> 63</td><td>ac</td><td>CH2CH2-</td><td>\ from^MeNN H and Me</td>

<td> 64</td><td>ac</td><td>CH2CH2-</td><td>\ from^MeMe</td>

<td> 65</td><td>ac</td><td>CH2CH2-</td><td>\ _ / H</td>

<td> 66</td><td>ac</td><td>CH2CH2-</td><td>et \ ^^ N 'Et H</td>

<td> 67</td><td>ac</td><td>~ ch₂ch₂~</td><td>^X'' N— (N-Me N ^^</td>

<td> 68</td><td>ac</td><td>CH2CH2-</td><td>"Et</td>

<td> 69</td><td>ac</td><td>CH2CH2-</td><td>-Ό-Ό</td>

<td> 70</td><td>ac</td><td>CH2CH2-</td><td></td>

<td> 71</td><td>ac</td><td>CH2CH2-</td><td>at U</td>

<td> 72</td><td>ac</td><td>CH2CH2-</td><td>at CL</td>

<td> 73</td><td>ac</td><td>CH2CH2-</td><td>O-Bu ^ 'NN</td>

160

<td> 74</td><td>ac</td><td>CH2CH2-</td><td>—N \ h</td>

<td> 75</td><td>ac</td><td>CH2CH2-</td><td>et \ / \ N et</td>

<td> 76</td><td>ac</td><td>CH2CH2-</td><td>NN iPr \. Pr</td>

<td> 77</td><td>ac</td><td>CH2CH2-</td><td></td>

<td> 78</td><td>ac</td><td>CH2CH2-</td><td>NN N0</td>

<td> 79</td><td>ac</td><td>CH2CH2-</td><td> \ /^MeNN</td>

<td> 80</td><td>ac</td><td>CH2CH2-</td><td>N-Me 0</td>

<td> 81</td><td>ac</td><td>CH2CH2-</td><td>-NH-Me IN</td>

<td> 82</td><td>ac</td><td>CH2CH2-</td><td>-CH2CH3</td>

Example 83-193

The compound obtained in Example 18 (as the hydrochloride salt, 20 mg, 25 μΜ), the corresponding carboxylic acid compound (30 μΜ),

MP-carbonate (25 pM, from Argonaut company, macroporous polystyrene anion exchange resin) and H0Bt-H₂0 (4.5 mg, 29 μΜ), added to methylene chloride - DMF (0.5 mL - 0.1 mL) and obtained

161 the suspension was shaken at room temperature for 1 hour. Then, PS-carbodiimide (33 μΜ, from Argonaut company, N-cyclohexylcarbodiimido-N'-propyloxymethyl-polystyrene) was added to the reaction mixture, and the mixture was shaken at room temperature overnight (about 18 hours). PS-isocyanate (75 μΜ, from Argonaut company, Polystyrene methylisocyanate) was added to the reaction solution, and the mixture was shaken at room temperature for 3 hours, after which the unreacted starting compound was removed. The MP-carbonate was then filtered off and washed with 0.2 ml methylene chloride and 0.2 ml DMF. Methylene chloride was evaporated from the combined filtrate and washes by flushing with nitrogen gas, and the residue was purified by separation by HPLC under the following conditions to give the product. After purification, the fraction solution was freeze-dried and the freeze-dried product was weighed and the structure analyzed by LC / MS analysis under the following conditions.

&lt;HPLC conditions&gt;

<td>Column: CAPCELL</td><td>PITCH</td><td>C18</td><td>(UG</td><td> 120</td><td>S-5</td><td>20 mm x</td><td> 50</td><td>mm)</td>

<td>(for purification)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>CAPCELL</td><td>PITCH</td><td>C18</td><td>(UG</td><td> 120</td><td>S-3</td><td>3.0 mm x</td><td> 50</td><td>mm)</td>

<td>(for analysis)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2">Eluent: a mixture</td><td> 0,</td><td> 05%</td><td>TFA-</td><td>MeCN</td><td> 0,05%</td><td>TFA</td><td>-H2O</td>

(possibly by changing the ratio)

Flow rate: 36 ml / min (for purification)

1.8 ml / min (for analysis) &lt;LC / MS analytical conditions&gt;

System: Waters Alliance 2795, Waters ZQ MS Detector: ESI positive

According to the above procedure, each compound shown in Table 7 below was synthesized. Each table was described

162 total calculated mass number and observed LC / MS result ([M + H]).

Table 7

N

<img file="PL1740574T3_D0098.tif" />

<img file="PL1740574T3_D0099.tif" />

<td>Example No.</td><td>R</td><td>calculated number mass</td><td>observed Value [M + H]</td>

<td> 83</td><td></td><td> 635</td><td> 636</td>

<td> 84</td><td></td><td> 635</td><td> 636</td>

<td></td><td>NHAc</td><td></td><td></td>

<td> 85</td><td>_N</td><td> 607</td><td> 608</td>

<td></td><td></td><td></td><td></td>

<td> 86</td><td>h</td><td> 579</td><td> 580</td>

<td></td><td></td><td></td><td></td>

<td> 87</td><td>_N</td><td> 579</td><td> 580</td>

<td></td><td></td><td></td><td></td>

163

<td> 88</td><td></td><td colspan="2">N Q</td><td> 579</td><td> 580</td>

<td> 89</td><td colspan="2"></td><td></td><td> 593</td><td> 594</td>

<td> 90</td><td colspan="2"></td><td> 0'</td><td> 593</td><td> 594</td>

<td> 91</td><td colspan="2"></td><td> 0</td><td> 593</td><td> 594</td>

<td> 92</td><td colspan="3"></td><td> 644</td><td> 645</td>

<td> 93</td><td colspan="3">/ Ph / 0</td><td> 608</td><td> 609</td>

<td> 94</td><td colspan="3">^^^ / Ph</td><td> 606</td><td> 607</td>

<td> 95</td><td colspan="3"></td><td> 604</td><td> 605</td>

<td> 96</td><td colspan="3"></td><td> 622</td><td> 623</td>

<td> 97</td><td colspan="3">Y</td><td> 568</td><td> 569</td>

<td> 98</td><td colspan="3">Y</td><td> 584</td><td> 585</td>

<td> 99</td><td></td><td colspan="2">ABOUT ABOUT</td><td> 568</td><td> 569</td>

164

<td rowspan="2"> 100</td><td colspan="2">S</td><td rowspan="2"> 584</td><td rowspan="2"> 585</td>

<td></td><td>at</td>

<td> 101</td><td></td><td>S</td><td> 598</td><td> 599</td>

<td></td><td></td><td>V</td><td></td><td></td>

<td> 102</td><td></td><td></td><td> 598</td><td> 599</td>

<td></td><td></td><td>^ Z / S</td><td></td><td></td>

<td> 103</td><td></td><td></td><td> 620</td><td> 621</td>

<td></td><td></td><td></td><td></td><td></td>

<td> 104</td><td colspan="2"></td><td> 634</td><td> 635</td>

<td> 105</td><td colspan="2">Me</td><td> 516</td><td> 517</td>

<td> 106</td><td colspan="2">et</td><td> 530</td><td> 531</td>

<td> 107</td><td colspan="2">n-Pr</td><td> 544</td><td> 545</td>

<td> 108</td><td colspan="2">i-Pr</td><td> 544</td><td> 545</td>

<td> 109</td><td></td><td> 0</td><td> 570</td><td> 571</td>

<td> 110</td><td></td><td></td><td> 584</td><td> 585</td>

<td> 111</td><td colspan="2">"X&gt;</td><td> 584</td><td> 585</td>

<td> 112</td><td colspan="2"></td><td> 598</td><td> 599</td>

<td> 113</td><td colspan="2"></td><td> 650</td><td> 651</td>

<td> 114</td><td colspan="2">υ F &lt; 1</td><td> 627</td><td> 628</td>

165

<img file="PL1740574T3_D0100.tif" />

166

<img file="PL1740574T3_D0101.tif" />

167

<img file="PL1740574T3_D0102.tif" />

168

<td> 142</td><td colspan="3">NH s.</td><td> 617</td><td> 618</td>

<td> 143</td><td colspan="3">Λ&gt;</td><td> 567</td><td> 568</td>

<td> 144</td><td colspan="3">-Α</td><td> 619</td><td> 620</td>

<td> 145</td><td colspan="3"></td><td> 585</td><td> 586</td>

<td> 146</td><td colspan="3">ΑΟ</td><td> 618</td><td> 619</td>

<td> 147</td><td></td><td> 0</td><td>Me</td><td> 606</td><td> 607</td>

<td> 148</td><td></td><td></td><td>cl</td><td> 627</td><td> 628</td>

<td> 149</td><td colspan="3"></td><td> 654</td><td> 655</td>

<td> 150</td><td colspan="3">ABOUT</td><td> 645</td><td> 646</td>

<td> 151</td><td colspan="3">Ah</td><td> 624</td><td> 625</td>

169

<td> 152</td><td colspan="3">ABOUT</td><td> 634</td><td> 635</td>

<td> 153</td><td colspan="3"></td><td> 645</td><td> 646</td>

<td> 154</td><td>S -0</td><td> 0</td><td></td><td> 634</td><td> 635</td>

<td> 155</td><td></td><td></td><td></td><td> 605</td><td> 606</td>

<td> 156</td><td colspan="3">HZN</td><td> 647</td><td> 648</td>

<td> 157</td><td colspan="3">ABOUT</td><td> 647</td><td> 648</td>

<td> 158</td><td></td><td>N H</td><td>ABOUT</td><td> 677</td><td> 678</td>

<td> 159</td><td colspan="3"></td><td> 705</td><td> 706</td>

170

<img file="PL1740574T3_D0103.tif" />

171

<img file="PL1740574T3_D0104.tif" />

172

<td> 178</td><td colspan="2">Me r4 Me</td><td> 613</td><td> 614</td>

<td> 179</td><td></td><td>S ) N H</td><td> 603</td><td> 604</td>

<td> 180</td><td></td><td>NOH Y \ / cl</td><td> 630</td><td> 631</td>

<td> 181</td><td colspan="2">et et</td><td> 601</td><td> 602</td>

<td> 182</td><td colspan="2">H</td><td> 559</td><td> 560</td>

<td> 183</td><td colspan="2">Me OH Me</td><td> 618</td><td> 619</td>

<td> 184</td><td colspan="2">/ Ph H</td><td> 607</td><td> 608</td>

<td> 185</td><td colspan="2">ac Y</td><td> 613</td><td> 614</td>

<td> 186</td><td colspan="2">Me / 3</td><td> 581</td><td> 582</td>

<td> 187</td><td colspan="2">^Me ^ o ___ N Y Me</td><td> 597</td><td> 598</td>

173

<td> 18 8</td><td colspan="3"></td><td> 594</td><td> 595</td>

<td> 189</td><td></td><td>φ</td><td></td><td> 580</td><td> 581</td>

<td></td><td></td><td>'' '' N-</td><td></td><td></td><td></td>

<td> 190</td><td></td><td></td><td>Me</td><td> 594</td><td> 595</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td> 191</td><td></td><td colspan="2"> 0 ⁰| 'N^;N0 H</td><td> 612</td><td> 613</td>

<td> 192</td><td colspan="3">_NN</td><td> 584</td><td> 585</td>

<td> 193</td><td colspan="3"></td><td> 623</td><td> 624</td>

<td></td><td></td><td colspan="2">C0NH2</td><td></td><td></td>

Example 194-201

To a 20 mg (25 μΜ) solution of the compound obtained in

Example 18 (as the hydrochloride) in 0.2 ml DMF was added MPW carbonate (125 μΜ) and the mixture was shaken at room temperature for 3 hours. The reaction mixture was then filtered, the filtrate was added to a solution of the corresponding sulfonyl chloride compound in 0.1 mL DMF (50 μΜ), then 8.7 µL of diisopropylethylamine (50 μΜ) was added to the mixture, and the resulting mixture was shaken at room temperature overnight (at approximately 18 hours).

174

The reaction solution was introduced into HPLC similar to the conditions described in the above-mentioned Examples 83-193 and purified to separate the product. After purification, the fractional solution was freeze-dried, the freeze-dried product was weighed and the structure analyzed by LC / MS analysis under the conditions described in Examples 83-193. The structures, calculated mass numbers and observed LC / MS results of each compound obtained are shown in Table 8.

Table 8

N

<img file="PL1740574T3_D0105.tif" />

N

<img file="PL1740574T3_D0106.tif" />

N

ABOUT^SABOUT

<td>Example No.</td><td colspan="2">R</td><td>number mass calculated</td><td>Value observed [M + H]</td>

<td> 194</td><td></td><td></td><td> 644</td><td> 645</td>

<td> 195</td><td>ph</td><td></td><td> 614</td><td> 615</td>

<td> 196</td><td>N</td><td>Me</td><td> 618</td><td> 619</td>

<td> 197</td><td></td><td>L '</td><td> 628</td><td> 629</td>

175

<td> 198</td><td>n-hexadecyl</td><td> 763</td><td> 764</td>

<td> 199</td><td>Me</td><td> 552</td><td> 553</td>

<td> 200</td><td>n-Bu</td><td> 594</td><td> 595</td>

<td> 201</td><td>et</td><td> 566</td><td> 567</td>

Example 202 - 243

A solution of 16 mg of the compound obtained in Example e 18 (as the hydrochloride salt, 20 μΜ), the corresponding alkyl halide (22 μΜ), saturated aqueous potassium carbonate (100 μΜ) in 0.2 ml DMF was shaken at room temperature overnight (approximately 18 hours). 0.2 ml DMF was added to the reaction solution, and thus the solution was diluted, after which the diluted solution was purified to separate the product by HPLC under conditions similar to those described in the abovementioned Examples 83-193. Then, after purification, the fraction solution was freeze-dried and the freeze-dried product was weighed and the structure was analyzed by LC / MS as mentioned above.

The structures and calculated mass numbers and observed LC / MS results of each compound obtained are shown in Table 9. Table 9

N

<img file="PL1740574T3_D0107.tif" />

N

<img file="PL1740574T3_D0108.tif" />

N _FROM1

176

<img file="PL1740574T3_D0109.tif" />

177

<td> 213</td><td>N</td><td>N^NN N (CH2) 5CH3</td><td> 640</td><td> 641</td>

<td> 214</td><td></td><td>ABOUT</td><td> 569</td><td> 570</td>

<td></td><td>N</td><td></td><td></td><td></td>

<td></td><td>χ</td><td>Me</td><td></td><td></td>

<td> 215</td><td>Me</td><td>N</td><td> 583</td><td> 584</td>

<td></td><td></td><td> \</td><td></td><td></td>

<td></td><td></td><td>ABOUT^ABOUT</td><td></td><td></td>

<td></td><td></td><td>Me</td><td></td><td></td>

<td> 216</td><td colspan="2"></td><td> 592</td><td> 593</td>

<td> 217</td><td colspan="2">n-Bu</td><td> 530</td><td> 531</td>

<td> 218</td><td colspan="2">i-Bu</td><td> 530</td><td> 531</td>

<td> 219</td><td colspan="2"></td><td> 565</td><td> 566</td>

<td></td><td colspan="2">\ AJ</td><td></td><td></td>

<td> 220</td><td></td><td> /=\</td><td> 604</td><td> 605</td>

<td></td><td>N^N</td><td>'ά #</td><td></td><td></td>

<td></td><td></td><td>yg</td><td></td><td></td>

<td></td><td></td><td>N</td><td></td><td></td>

<td></td><td></td><td>H</td><td></td><td></td>

<td> 221</td><td colspan="2"></td><td> 565</td><td> 566</td>

<td></td><td></td><td>N</td><td></td><td></td>

<td> 222</td><td></td><td>S</td><td> 647</td><td> 648</td>

<td></td><td>-C</td><td></td><td></td><td></td>

<td> 223</td><td>ABOUT</td><td></td><td> 559</td><td> 560</td>

<td></td><td>. AND</td><td>Me</td><td></td><td></td>

<td></td><td></td><td>_N Me AND</td><td></td><td></td>

<td></td><td></td><td>Me</td><td></td><td></td>

178

<td> 224</td><td colspan="2">ABOUT ^^^^ nh₂</td><td> 531</td><td> 532</td>

<td> 225</td><td></td><td></td><td> 584</td><td> 585</td>

<td> 226</td><td colspan="2">Me Me</td><td> 545</td><td> 546</td>

<td> 227</td><td>'""ABOUT</td><td></td><td> 585</td><td> 586</td>

<td> 228</td><td colspan="2"></td><td> 587</td><td> 588</td>

<td> 229</td><td colspan="2"></td><td> 532</td><td> 533</td>

<td> 230</td><td colspan="2"> \/-'\/''-0^H</td><td> 546</td><td> 547</td>

<td> 231</td><td colspan="2">\ / \ / Et^Nt</td><td> 573</td><td> 574</td>

<td> 232</td><td colspan="2"></td><td> 608</td><td> 609</td>

<td> 233</td><td>AT</td><td></td><td> 599</td><td> 600</td>

<td> 234</td><td colspan="2">H</td><td> 613</td><td> 614</td>

179

<td> 235</td><td colspan="4"></td><td> 604</td><td> 605</td>

<td> 236</td><td colspan="4">i-Pr N 1 i-Pr</td><td> 601</td><td> 602</td>

<td> 237</td><td colspan="4">NH2 \ -Anh</td><td> 530</td><td> 531</td>

<td> 238</td><td colspan="4">-ο</td><td> 599</td><td> 600</td>

<td> 239</td><td></td><td colspan="3">ABOUT^ABOUT| "H WELL H</td><td> 598</td><td> 599</td>

<td> 240</td><td></td><td>τ^N</td><td></td><td></td><td> 615</td><td> 616</td>

<td> 241</td><td></td><td>[^ Ίι N</td><td colspan="2">OH</td><td> 595</td><td> 596</td>

<td> 242</td><td colspan="3">Me</td><td></td><td> 599</td><td> 600</td>

<td> 243</td><td></td><td colspan="3">S Q</td><td> 571</td><td> 572</td>

180

Example 244 - 298

To a 20 mg (25 μΜ) solution of the compound obtained in

Example 18 (as the hydrochloride salt) in 0.6 ml of the mixture

THF-DMF (3: 1) the corresponding aldehyde compound (28 μΜ) in 28 μΐ DMF and 7 μΐ (125 μΜ) of acetic acid was added. MP-cyanoborohydride (63 μΜ, Argonaut Company, Macroporous triethylammonium methylpolystyrene cyanoborohydride) was added to the reaction mixture, and the mixture was shaken at room temperature for 2 days. MP-cyanoborohydride was filtered off, the filtrate was applied to an HPLC column similar to the conditions described in Examples 83-193 above and purified to separate the product. Then, after purification, the fraction solution was freeze-dried, the freeze-dried product was weighed and the structure was analyzed by LC / MS as mentioned above.

The structures and calculated mass numbers and observed LC / MS results of each compound obtained are shown in Table 10.

Table 10

NHAc

Z1

181

<td>Example No.</td><td colspan="2">FROM¹</td><td>calculated number mass</td><td>observed Value [M + H]</td>

<td> 244</td><td></td><td>ABOUT ABOUT</td><td> 554</td><td> 555</td>

<td> 245</td><td colspan="2">HN a0</td><td> 554</td><td> 555</td>

<td> 246</td><td></td><td>rv Me ABOUT</td><td> 568</td><td> 569</td>

<td> 247</td><td colspan="2">JO</td><td> 570</td><td> 571</td>

<td> 248</td><td colspan="2">JO Me</td><td> 584</td><td> 585</td>

<td> 249</td><td></td><td>NH</td><td> 603</td><td> 604</td>

<td> 250</td><td colspan="2"></td><td> 604</td><td> 605</td>

<td> 251</td><td></td><td>N Li</td><td> 615</td><td> 616</td>

<td> 252</td><td></td><td>OO</td><td> 615</td><td> 616</td>

182

<td> 253</td><td></td><td>NH L, C '^h</td><td> 630</td><td> 631</td>

<td> 254</td><td colspan="2"></td><td> 617</td><td> 618</td>

<td> 255</td><td colspan="2"></td><td> 663</td><td> 664</td>

<td> 256</td><td></td><td>et cr</td><td> 652</td><td> 653</td>

<td> 257</td><td colspan="2"></td><td> 580</td><td> 581</td>

<td> 258</td><td></td><td>1 A-COOH S</td><td> 614</td><td> 615</td>

<td> 259</td><td></td><td>1 2 — sat₃h ABOUT</td><td> 634</td><td> 635</td>

<td> 260</td><td colspan="2"></td><td> 634</td><td> 635</td>

<td> 261</td><td></td><td>f \ -Cl S</td><td> 604</td><td> 605</td>

183

<img file="PL1740574T3_D0110.tif" />

184

<img file="PL1740574T3_D0111.tif" />

185

<img file="PL1740574T3_D0112.tif" />

186

<img file="PL1740574T3_D0113.tif" />

187

<img file="PL1740574T3_D0114.tif" />

Example 299-416

A suspension of 24 mg (50 pM) of the compound obtained in Example 45, the corresponding primary or secondary alkylamine compound (100 pM) and 8.9 mg HOBt - H2O (58 pM) in a mixture of ethylene chloride - DMF (0.5 ml - 0.2 mL) was shaken at room temperature for 10 minutes. When a salt was used as the starting material of the amino compound, an equimolar amount of MP-Carbonate (Argonaut Company) was added to the reaction medium. Then PSkarbodiimide (Argonaut Company, 67 pM) was added to the reaction mixture and the mixture was shaken at room temperature overnight (approximately 18 hours).

The reaction mixture was then filtered and washed with DMF (0.15 mL) to remove resin, PS-carbodiimide and MPCarbonate, if used. The filtrate and the rinsing solution were combined, ethylene chloride was evaporated under a stream of nitrogen gas, the residue was diluted with 0.15 ml DMF and the diluted solution was purified to separate the product by HPLC under conditions similar to those described in Examples 83-193 above. After cleaning the fraction solution

188 lyophilized, the lyophilized product was weighed and the structure analyzed by LC / MS analysis as mentioned above.

The structures, calculated mass numbers, and observed LC / MS results of each compound obtained are shown in Table 11.

Table 11

NHAc

N

<img file="PL1740574T3_D0115.tif" />

<td>Example No.</td><td>FROM³</td><td>calculated mass number</td><td>observed Value [M + H]</td>

<td> 299</td><td> \^^;^ χ J N</td><td> 607</td><td> 608</td>

<td> 300</td><td>n-Bu</td><td> 572</td><td> 573</td>

<td> 301</td><td>Me NN Me</td><td> 587</td><td> 588</td>

<td> 302</td><td>N V / \ -d</td><td> 584</td><td> 585</td>

189

<td> 303</td><td colspan="2">OH N X</td><td> 567</td><td> 568</td>

<td> 304</td><td colspan="2">P OH</td><td> 531</td><td> 532</td>

<td> 305</td><td>H</td><td>N □</td><td> 538</td><td> 539</td>

<td> 306</td><td>ABOUT /</td><td>N NMe</td><td> 627</td><td> 628</td>

<td> 307</td><td></td><td>X OH</td><td> 607</td><td> 608</td>

<td> 308</td><td colspan="2">Me Me</td><td> 620</td><td> 621</td>

<td> 309</td><td colspan="2">/ K 3 and rA</td><td> 717</td><td> 718</td>

190

<td> 310</td><td colspan="2">"Ό π NN</td><td> 607</td><td> 608</td>

<td> 311</td><td>^N</td><td>Me N_NN^NN</td><td> 639</td><td> 640</td>

<td> 312</td><td colspan="2">i-Pr N ^ ^^^^^N\_i-Pr_H i-Pr</td><td> 574</td><td> 575</td>

<td> 313</td><td colspan="2">H °^Nt^NS N 9. NMe Me</td><td> 750</td><td> 751</td>

<td> 314</td><td colspan="2">oo</td><td> 593</td><td> 594</td>

<td> 315</td><td></td><td>about.</td><td> 538</td><td> 539</td>

<td> 316</td><td colspan="2"> °^/^NH2 NPh</td><td> 649</td><td> 650</td>

191

<img file="PL1740574T3_D0116.tif" />

192

<td> 326</td><td>Ο /</td><td>α Me</td><td> 613</td><td> 614</td>

<td> 327</td><td colspan="2">AT</td><td> 627</td><td> 628</td>

<td> 328</td><td colspan="2">OH N XH</td><td> 535</td><td> 536</td>

<td> 329</td><td colspan="2">\ from^MeNN Me NMe Me</td><td> 617</td><td> 618</td>

<td> 330</td><td colspan="2">Me Et</td><td> 574</td><td> 575</td>

<td> 331</td><td colspan="2">et '' '' -Ν ^ - 'Χ^Net ^et</td><td> 574</td><td> 575</td>

<td> 332</td><td>ABOUT /</td><td>γ'ί N</td><td> 594</td><td> 595</td>

<td> 333</td><td colspan="2">l ^^ ^^ N Ph</td><td> 606</td><td> 607</td>

<td> 334</td><td colspan="2">N H^H</td><td> 538</td><td> 539</td>

193

335

336

337

338

339

340

<img file="PL1740574T3_D0117.tif" />

<img file="PL1740574T3_D0118.tif" />

<img file="PL1740574T3_D0119.tif" />

'Me

Me

<img file="PL1740574T3_D0120.tif" />

<img file="PL1740574T3_D0121.tif" />

Me _NMe

640

598

627

658

677

641

599

628

659

678

N

Me

ph

<img file="PL1740574T3_D0122.tif" />

ph

676

677

et _Net

643

644

N

Me

et

341

<img file="PL1740574T3_D0123.tif" />

194

<td> 342</td><td>NN</td><td> 633</td><td> 634</td>

<td> 343</td><td> \/ⁿll</td><td> 683</td><td> 684</td>

<td> 344</td><td> \ /^phN HN CKA</td><td> 649</td><td> 650</td>

<td> 345</td><td>Oy \ CN</td><td> 617</td><td> 618</td>

<td> 346</td><td>\ from^MeNN L me ph</td><td> 622</td><td> 623</td>

<td> 347</td><td>Li) «G vj ABOUT /</td><td> 649</td><td> 650</td>

<td> 348</td><td>Me N Me ph</td><td> 608</td><td> 609</td>

<td> 349</td><td>-N \ —Ph</td><td> 592</td><td> 593</td>

195

<img file="PL1740574T3_D0124.tif" />

196

<img file="PL1740574T3_D0125.tif" />

197

<td> 365</td><td colspan="2">CX&gt;</td><td> 607</td><td> 608</td>

<td> 366</td><td>N</td><td>N</td><td> 621</td><td> 622</td>

<td> 367</td><td colspan="2">NOPh kXv H</td><td> 663</td><td> 664</td>

<td> 368</td><td>N</td><td>^N 88</td><td> 621</td><td> 622</td>

<td> 369</td><td colspan="2">cr¹ /</td><td> 671</td><td> 672</td>

<td> 370</td><td colspan="2">N^C1 ^NABOUT</td><td> 657</td><td> 658</td>

<td> 371</td><td colspan="2">-N \ —Et</td><td> 544</td><td> 545</td>

<td> 372</td><td colspan="2">OH</td><td> 560</td><td> 561</td>

198

<td> 373</td><td colspan="2">NN</td><td> 627</td><td> 628</td>

<td> 374</td><td>H</td><td>N^N Me Me</td><td> 587</td><td> 588</td>

<td> 375</td><td colspan="2">OH</td><td> 608</td><td> 609</td>

<td> 376</td><td>AT</td><td>OH</td><td> 531</td><td> 532</td>

<td> 377</td><td colspan="2"></td><td> 545</td><td> 546</td>

<td> 378</td><td></td><td>OH</td><td> 545</td><td> 546</td>

<td> 379</td><td>ABOUT</td><td>ph H</td><td> 621</td><td> 622</td>

<td> 380</td><td>H</td><td>et_Net about</td><td> 558</td><td> 559</td>

<td> 381</td><td colspan="2">N H</td><td> 544</td><td> 545</td>

199

<td> 382</td><td colspan="3">NN NU</td><td> 558</td><td> 559</td>

<td> 383</td><td colspan="3">ABOUT /</td><td> 560</td><td> 561</td>

<td> 384</td><td colspan="3">NNⁿ about</td><td> 574</td><td> 575</td>

<td> 385</td><td colspan="2">ABOUT /</td><td>CF3</td><td> 675</td><td> 676</td>

<td> 386</td><td></td><td>N^N</td><td>Me N Me</td><td> 657</td><td> 658</td>

<td> 387</td><td></td><td colspan="2">N NMe NMe</td><td> 643</td><td> 644</td>

<td> 388</td><td colspan="3">in \ t</td><td> 586</td><td> 587</td>

<td> 389</td><td colspan="3">Me ./ \. ^ W \ e</td><td> 558</td><td> 559</td>

200

<td> 390</td><td colspan="3">-OKD</td><td> 612</td><td> 613</td>

<td> 391</td><td colspan="3">N Ph -Ό</td><td> 620</td><td> 621</td>

<td> 392</td><td colspan="2">at</td><td>0 Ka-^phMe</td><td> 662</td><td> 663</td>

<td> 393</td><td colspan="2"></td><td>ph N Me</td><td> 648</td><td> 649</td>

<td> 394</td><td colspan="3">^ί^^ί€^&gt;</td><td> 654</td><td> 655</td>

<td> 395</td><td colspan="2">about /</td><td>N Ph Me</td><td> 634</td><td> 635</td>

<td> 396</td><td>N k</td><td colspan="2">ph and Me</td><td> 620</td><td> 621</td>

<td> 397</td><td colspan="3">m ph</td><td> 606</td><td> 607</td>

<td> 398</td><td>N Me</td><td colspan="2">ac N at</td><td> 586</td><td> 587</td>

201

<img file="PL1740574T3_D0126.tif" />

202

<td rowspan="2"> 407</td><td rowspan="2"> /</td><td colspan="2"> °</td><td rowspan="2"> 602</td><td rowspan="2"> 603</td>

<td>/ 9Λ</td><td> °</td>

<td> 408</td><td></td><td></td><td> "\</td><td> 600</td><td> 601</td>

<td></td><td> 9</td><td>ΑΧ-</td><td> °</td><td></td><td></td>

<td> 409</td><td></td><td>Me</td><td></td><td> 566</td><td> 567</td>

<td></td><td></td><td>N</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Me</td><td></td><td></td>

<td></td><td>N</td><td></td><td></td><td></td><td></td>

<td></td><td>H</td><td></td><td></td><td></td><td></td>

<td> 410</td><td>NH</td><td></td><td></td><td> 712</td><td> 713</td>

<td></td><td> 1</td><td> °</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>Ί</td><td></td><td></td>

<td></td><td></td><td></td><td>NPh</td><td></td><td></td>

<td> 411</td><td> / \</td><td>AND</td><td></td><td> 616</td><td> 617</td>

<td></td><td> 9</td><td> /</td><td>_°°</td><td></td><td></td>

<td> 412</td><td></td><td></td><td>F</td><td> 668</td><td> 6 69</td>

<td></td><td>N</td><td>9 tf</td><td>'k</td><td></td><td></td>

<td></td><td></td><td>/ X &lt;</td><td> °</td><td></td><td></td>

<td> 413</td><td> / \</td><td>&gt; c</td><td>about</td><td> 600</td><td> 601</td>

<td></td><td> 9</td><td>X \ J</td><td>Me</td><td></td><td></td>

<td> 414</td><td></td><td></td><td>XX</td><td> 640</td><td> 641</td>

<td></td><td>N</td><td> &gt; (</td><td></td><td></td><td></td>

<td></td><td>k.</td><td>^N</td><td></td><td></td><td></td>

203

<td> 415</td><td> / /-</td><td>ABOUT</td><td> 588</td><td> 589</td>

<td> 416</td><td> / /-</td><td>χ ac</td><td> 558</td><td> 559</td>

Examples of pharmacological studies using the compounds of the invention are described below.

(1) c-AMP-generating activity in cells expressing adenosine A2a receptor

The test was conducted as follows with respect to the method disclosed in the reference (Klotz kN et al., NaunynSchmiedeberg^ls Arch. Pharmacol., (1998) 357, 1-9; Shryock JC et al., Molecular Pharmacology, (1998) 53, 886-893).

As for cells, HEK293 cells expressing the adenosine A2a receptor (human) (PerkinElmer Life Sciences, Code No. RBHA2AC) were used.

Regarding the culture medium, Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS (fetal bovine serum) and 1 mM sodium pyruvate was used.

Cells were placed in a 96-well plate (1x10⁵/ well) and grown overnight. After removal of the supernatant, 0.1 ml DMEM (without FBS) containing 20 mM HEPES, 0.1 mM IBMX (3-isobutyl-1-methyl-xanthine) and 2 units / ml adenosine deaminase were added to each well and incubated at 37 ° C within 30 minutes. 0.1 ml of culture medium containing the appropriate concentration of DMSO test compound was added to each well, incubated for an additional 30 minutes. After removing the supernant, cytolytic solution was added to terminate the reaction. The amount of c-AMP in each well was measured

204 using the c-AMP enzyme immunoassay (EIA) (Amersham Biosciences, Code No. RPN225).

The same test was repeated using CGS-21680 ((2-p-carboxyethyl) phenethylamino-5'-N-ethylcarboxamido-adenosine hydrochloride) (Sigma, code C141) as a reference compound.

The amount of c-AMP obtained in the medium, induced by 1 μM Reference compound, was defined as 100%. The concentration of the analyzed compound in the medium giving 50% c-AMP was calculated as the EC50 value.

The results of the above test obtained using the following compounds of the invention, prepared in the above-mentioned Examples, are shown in Table 12 below. In addition, the Table also shows the results of the same test using the compound described in Example 6 according to the application WO 03/053441 A1 (referred to Reference Compound A) and the compound described in Example 1 of WO 03/008384 A1 (related to Reference Compound B) having the following structures.

&lt;Reference Compound A&gt;

<img file="PL1740574T3_D0127.tif" />

205 &lt;Reference Compound B&gt;

HN

<img file="PL1740574T3_D0128.tif" />

Table 12

<td>Test compound (Example No.)</td><td>Action (EC50, nM)</td><td>agonist</td><td>A2a</td>

<td> 1</td><td colspan="3"> 39,6</td>

<td> 2</td><td colspan="3"> 11,9</td>

<td> 3</td><td colspan="3"> 65,7</td>

<td> 4</td><td colspan="3"> 879</td>

<td> 8</td><td colspan="3"> 34,8</td>

<td> 9</td><td colspan="3"> 9,0</td>

<td> 10</td><td colspan="3"> 19,1</td>

<td> 11</td><td colspan="3"> 395</td>

<td> 13</td><td colspan="3"> 13,5</td>

<td> 14</td><td colspan="3"> 39,6</td>

<td> 17</td><td colspan="3"> 6,8</td>

<td> 19</td><td colspan="3"> 7,4</td>

<td> 21</td><td colspan="3"> 10,6</td>

206

<td> 26</td><td> 30,7</td>

<td> 28</td><td> 8,2</td>

<td> 33</td><td> 48,0</td>

<td> 41</td><td> 23,0</td>

<td> 42</td><td> 10,0</td>

<td> 46</td><td> 7,4</td>

<td> 48</td><td> 29,1</td>

<td> 52</td><td> 7,0</td>

<td> 54</td><td> 5,3</td>

<td> 55</td><td> 5,5</td>

<td> 56</td><td> 5,1</td>

<td> 57</td><td> 3,4</td>

<td> 58</td><td> 38,0</td>

<td> 60</td><td> 2,8</td>

<td> 61</td><td> 3,4</td>

<td> 62</td><td> 5,1</td>

<td> 64</td><td> 4,3</td>

<td> 66</td><td> 5,2</td>

<td> 67</td><td> 6,8</td>

<td> 68</td><td> 7,5</td>

<td> 69</td><td> 7,0</td>

<td> 70</td><td> 8,8</td>

<td> 72</td><td> 13,6</td>

<td> 74</td><td> 2,5</td>

<td> 75</td><td> 3,0</td>

<td> 16</td><td> 7,6</td>

<td> 11</td><td> 9,5</td>

<td> 78</td><td> 6,0</td>

<td> 79</td><td> 8,4</td>

<td> 80</td><td> 2,4</td>

<td> 82</td><td> 8,2</td>

<td>Reference Compound A</td><td> &gt;1000</td>

<td>Reference Compound B</td><td> 14,3</td>

207

Based on the results shown in Table 12, it is evident that all compounds of the invention have potent A2a receptor stimulating activity.

(2) Agonist activity of adenosine A1

The study was conducted as mentioned below with reference to the method disclosed in the literature (Shryock JC et al., Molecular Pharmacology, (1998) 53, 886-893; Ito H. et al., European Journal of Pharmacology, (1999) 365, 309- 315). The cerebral cortex of male Wistar rats (Charles River Japan, Inc) was excised, Tris buffer (50 mM Tris-HCl: pH 7.4) was added, homogenized and then centrifuged (1000 xg, 10 min). The supernatant was taken and centrifuged (20,000 xg, 20 min). After removal of the supernatant, the pellet was resuspended in Tris buffer and centrifuged again (20,000 xg, 20 min). After removal of the supernatant, the pellet was suspended in Tris buffer containing 2 units / mL ADA (adenosine deaminase) and stored at -80 ° C until used as a liquid cell membrane preparation for subsequent studies.

The above liquid cell membrane preparation in an amount corresponding to 10 μg of the cell membrane was added to Tris buffer containing 5 mM MgCl₂, 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 the mixture was incubated at 25 ° C for 30 minutes. Then [³⁵S] GTPyS (guanosine 5'- [γ-thio] triphosphate) (final concentration: 0.4 nM) and test compound at the given concentration (which was calculated from the final concentration of the test compound) and the resulting mixture was incubated at 25 ° C for 45 minutes. The reaction mixture was filtered through a glass fiber filter (unifilter-96 GF / B, Perkin Elmer Life Sciences) to terminate the reaction. The filter was washed 5 times with ice-cold Tris buffer containing 5 mM MgCl₂. The radioactivity of the filter was measured using Top

208 count NXT (Perkin Elmer Life Sciences). Non-specific binding is shown as binding activity [³⁵S] GTPyS in the presence of 0.01 mM GTPyS.

Activity (%, A1 agonist activity) of each test compound was calculated based on the test results (binding activity [³⁵S] GTPyS) derived from 1 μM CPA (N⁶-cyclopentyloadenosine, Sigma, code C-8031) in a standard that was counted as 100%.

Table 13 below shows the results in 1 μΝ, 100 nM and 10 nM of test compounds of the invention (including their salts) from the above-mentioned examples. Also Table 13 indicates the results of control compounds A and B which are the same as used in the pharmacological study (1).

Table 13

<td rowspan="2">Test compound</td><td colspan="3">Al agonist activity (%) (calculated as a percentage up to 100% test with CPA 1 μM)</td>

<td>1 μM</td><td>100 nM</td><td>10 nM</td>

<td>Reference Union A</td><td> 79</td><td> 55</td><td> 14</td>

<td>Reference Association B</td><td> 77</td><td> 63</td><td> 20</td>

<td>The compound of the invention (Example No.) 46</td><td> 45</td><td> 26</td><td> 4</td>

<td> 62</td><td> 39</td><td> 30</td><td> 8</td>

<td> 75</td><td> 50</td><td> 22</td><td> 3</td>

<td> 76</td><td> 46</td><td> 14</td><td> 0</td>

<td> 77</td><td> 40</td><td> 18</td><td> 2</td>

<td> 79</td><td> 45</td><td> 12</td><td> 0</td>

209

As seen from the results shown in Table 13, the A1 receptor activating (A1 agonist activity) of the compounds of the invention is still lower than that of the control compounds. This finding indicates that the compounds of the invention may selectively act on the A2a adenosine receptor.

In testing compounds of the invention of all examples other than the compounds used in Table 13 above, it was observed that all compounds exhibited almost the same A1 agonist activity as the compounds of the invention shown in Table 13.

(3) Rabbit intraocular pressure test

Test compounds were dissolved in 10 mM phosphate buffer (pH 7.5) (here referred to "ophthalmic vehicle medium") and dropped in at the given concentration. In addition, compounds insoluble at this concentration were used as a suspension. White New Zealand female rabbits (KITAYAMA LABES Co., Ltd.) Weighing 2.0-4.0 kg were used.

Measurement of intraocular pressure was carried out using a Pneumatonometer (Model 30 Classic, Mentor company) without anesthesia. In addition, prior to the measurement of intraocular pressure, surface anesthesia was performed with 0.4% oxybuprocaine hydrochloride ("Benoxil" 0.4% ophthalmic solution, Santen Pharmaceutical Co., Ltd.).

Animals in which intraocular pressure was stable before instillation were selected and these animals were divided into groups of 4 animals in each group, 50 μΐ eye drops containing each test compound were administered to one eye, and the medium was administered to the other eye as into the eye control. The measurement of intraocular pressure was carried out before instillation and 0.5, 1, 2, 3, 4 and 6 hours after instillation. The effect on intraocular pressure is shown as the difference from before instillation (ΔΙΟΡ, mmHg, mean ± measurement error). Tables 14 and 15 below show results for compounds

210 controls A and B used as 1% suspension, which are the same as in the pharmacological study (1).

Table 14. Control compound A, 1% Ophthalmic Suspension (n = 4) (mm Hg)

<td></td><td colspan="6">ΔIOP (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>examined Eye</td><td> -1,5±0,8</td><td> -1,4±1,3</td><td> -2,3±1,4</td><td> -2,2±1,2</td><td> -1,9±1,9</td><td> 0,9±1,4</td>

<td>inspection Eye</td><td> 0,4±0,7</td><td> 0,5±0,7</td><td> -0,2±0,6</td><td> -0,4±0,4</td><td> -0,4±1,2</td><td> 1,1±1,2</td>

Table 15. Control compound B, 1% Ophthalmic Suspension (n = 4)

<td></td><td colspan="6">ΔIOP (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>examined Eye</td><td> 0,7±0,2</td><td> 0,6±0,2</td><td> -0,9±0,3</td><td> 0,6±0,2</td><td> 0,3±1,0</td><td> 0,2±0,2</td>

<td>inspection Eye</td><td> 1,0±0,7</td><td> 1,1±0,5</td><td> -0,4±0,7</td><td> 0,4±0,5</td><td> 0,4±0,9</td><td> 0,4±0,2</td>

The animals were pre-treated as mentioned above, among them animals were selected in which intraocular pressure was stable before instillation and these animals were divided into groups of 5 to 8 animals in each group. Each group was used for each of the compounds tested. The test compound was administered unilaterally into the eye of the test rabbit and intraocular pressure was measured. The medium was administered unilaterally to the eye of a control rabbit and intraocular pressure was measured. As mentioned above, the measurement of intraocular pressure was carried out before instillation and 0.5, 1, 2, 3-, 4 and 6 hours after instillation, and the effect on intraocular pressure was shown as the difference from before instillation (ΔΙΟΡ, mmHg, mean ± measurement error ).

Tables 16 to 32 below show the results for the control compound CGS-2168 0 and the compound of the invention (compound obtained in the examples), each of the compounds tested is summarized in a separate Table.

Table 16. CGS-2-1680 (Control compound), 0.3% Ophthalmic Suspension (n = 6)

<td></td><td>ΔΙΟΡ (mm</td><td colspan="5">hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -2,5±0,4</td><td> -6,3±0,6</td><td> -4,2±0,4</td><td> -3,5±0,4</td><td> -1,5±0,7</td><td> 0,3±0,4</td>

<td>Checklist Group</td><td> -1,1±0,7</td><td> -1,8±0,2</td><td> -0,9±0,5</td><td> -1,3±0,5</td><td> -0,3±0,9</td><td> 1,0±0,8</td>

Table 17. Compound of Example 2, 1% Ophthalmic Suspension (n = 8)

<td></td><td colspan="6">ΔΙΟΡ (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> 1,1±0,6</td><td> -3,1±0,6</td><td> -4,2±0,7</td><td> -4,0±0,9</td><td> -2,0±0,4</td><td> 0,4±0,9</td>

<td>Checklist Group</td><td> 0,6±0,4</td><td> -0,5±0,6</td><td> -0,6±0,8</td><td> -0,6±0,7</td><td> 1,4±0,3</td><td> 2,7±0,8</td>

212

Table 18. Relationship with

Ophthalmic Preparation (n = 6)

Example 14, 0.3% suspension

<td></td><td>ΔIOP (mm</td><td colspan="5">hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -0,3±1,2</td><td> -3,9±1,3</td><td> -4,4±1,0</td><td> -4,8±1,4</td><td> -4,3±1,0</td><td> -1,0±1,0</td>

<td>Checklist Group</td><td> -0,7±0,5</td><td> -0,6±1,0</td><td> -0,4±1,1</td><td> -0,2±1,0</td><td> 0,3±1,2</td><td> 1,2±1,4</td>

Table 19. Compound of Example 46, 0.01% Ophthalmic

Solution (n = 6)

<td></td><td>ΔIOP (mm</td><td colspan="5">hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td></td>

<td>tested Group</td><td> -0,6±0,6</td><td> -4,4±0,8</td><td> -4,9±0,6</td><td> -3,8±0,7</td><td> -2,9±0,5</td><td> -0,5±0,6</td>

<td>Checklist Group</td><td> 0,0±0,8</td><td> 0,0±0,6</td><td> 0,3±0,7</td><td> -0,1±0,9</td><td> 0,7±0,6</td><td> 3,5±0,5</td>

Table 20. Compound of Example 69, 0.01% Ophthalmic

Solution (n = 6)

<td></td><td>ΔIOP (mm</td><td colspan="5">hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested</td><td> -1,5±1,0</td><td> -4,9±0,7</td><td> -3,6±0,4</td><td> -3,8±0,7</td><td> -2,6±1,0</td><td> 0,5±0,9</td>

<td>Group</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Checklist</td><td> 0,5±0,5</td><td> -0,5±0,4</td><td> -0,1±0,5</td><td> 0,5±0,6</td><td> 0,6±0,5</td><td> 2,6±0,8</td>

<td>Group</td><td></td><td></td><td></td><td></td><td></td><td></td>

213

Table 21. Compound of Example 75, 0.01% Ophthalmic

Solution (n = 5)

<td></td><td colspan="6">ΔIOP (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -0,8±0,4</td><td> -5,1±0,5</td><td> -5,3±0,9</td><td> -4,0±0,9</td><td> -4,3±0,9</td><td> -1,3±0,4</td>

<td>Checklist Group</td><td> -0,1±0,3</td><td> -0,4±0,6</td><td> -1,3±0,6</td><td> -0,5±0,4</td><td> -0,2±0,6</td><td> 0,6±0,7</td>

Table 22. Compound of Example 76, 0.01% Ophthalmic

Solution (n = 5)

<td></td><td colspan="6">ΔIOP (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -3,7±0,5</td><td> -6,0±0,8</td><td> -5,7±0,1</td><td> -6,1±0,3</td><td> -5,2±0,4</td><td> -3,6±0,7</td>

<td>Checklist Group</td><td> -0,4±0,3</td><td> -0,3±0,4</td><td> -0,3±0,7</td><td> -0,4±0,4</td><td> -0,6±0,4</td><td> 0,2±0,7</td>

Table 23. Compound of Example 61, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td colspan="6">ΔIOP (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -0,5±0,4</td><td> -4,2±0,6</td><td> -4,5±0,7</td><td> -4,8±0,7</td><td> -4,4±0,7</td><td> -1,2±0,8</td>

<td>Checklist Group</td><td> -0,4±0,3</td><td> -0,9±0,6</td><td> -1,1±0,8</td><td> -1,4±0,6</td><td> -0,2±0,8</td><td> 1,3±1,0</td>

214

Table 24. Compound of Example 62, 0.03% Ophthalmic

Solution (n = 5)

<td></td><td colspan="6">ΔΙΟΡ (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -1,2±0,7</td><td> -4,7±0,5</td><td> -5,1±0,3</td><td> -4,9±0,3</td><td> -3,6±0,3</td><td> -1,0±0,6</td>

<td>Checklist Group</td><td> -0,5±0,6</td><td> -0,6±0,4</td><td> -1,0±0,4</td><td> -1,1±0,5</td><td> -0,8±0,2</td><td> 1,4±0,9</td>

Table 25. Compound of Example 64, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td>ΔΙΟΡ (mm</td><td colspan="5">hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -2,7±0,7</td><td> -4,9±0,5</td><td> -3,8±0,8</td><td> -3,2±0,9</td><td> -4,0±0,7</td><td> -1,8±0,4</td>

<td>Checklist Group</td><td> -0,3±0,7</td><td> -1,2±0,5</td><td> -0,7±0,5</td><td> -0,3±0,4</td><td> -0,6±0,6</td><td> 2,3±1,0</td>

Table 26. Compound of Example 66, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td colspan="6">ΔΙΟΡ (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -1,3±0,9</td><td> -4,0±0,6</td><td> -5,5±0,7</td><td> -5,0±0,5</td><td> -3,7±0,5</td><td> -1,8±0,5</td>

<td>contr a Group</td><td> -0,3±0,2</td><td> -0,5±0,3</td><td> -0,8±0,5</td><td> 0,0±0,4</td><td> 0,3±0,5</td><td> 1,6±0,4</td>

215

Table 27. Compound of Example 67, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td colspan="6">ΔIOP (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -1,1±1,0</td><td> -5,3±0,7</td><td> -4,6±0,7</td><td> -4,6±0,9</td><td> -4,2±0,7</td><td> -2,0±0,7</td>

<td>Checklist Group</td><td> -1,3±0,4</td><td> -1,3±0,3</td><td> -0,9±0,8</td><td> -1,0±0,4</td><td> -0,4±0,6</td><td> 1,9±0,5</td>

Table 28. Compound of Example 72, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td colspan="6">ΔIOP (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -1,9±0,6</td><td> -5,3±0,6</td><td> -4,7±0,6</td><td> -5,0±0,7</td><td> -4,0±1,0</td><td> -1,9±0,9</td>

<td>Checklist Group</td><td> -0,6±0,2</td><td> -0,7±0,3</td><td> -0,8±0,7</td><td> -0,2±0,7</td><td> 0,0±0,3</td><td> 1,5±0,5</td>

Table 29. Compound of Example 77, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td>ΔIOP (mm</td><td colspan="5">hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -0,8±0,5</td><td> -5,0±0,6</td><td> -5,1±0,4</td><td> -4,4±0,6</td><td> -4,9±0,7</td><td> -3,1±0,7</td>

<td>Checklist Group</td><td> -1,4±0,8</td><td> -1,3±0,4</td><td> -1,8±0,4</td><td> -1,2±0,6</td><td> -1,0±0,7</td><td> 0,5±0,6</td>

216

Table 30. Compound of Example 78, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td colspan="6">ΔΙΟΡ (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> 0,6±0,5</td><td> -3,3±0,4</td><td> -4,4±0,6</td><td> -4,3±0,9</td><td> -5,4±0,7</td><td> -3,2±0,9</td>

<td>Checklist Group</td><td> -0,1±0,3</td><td> -0,9±0,4</td><td> -0,9±0,5</td><td> -0,1±0,3</td><td> -0,8±0,6</td><td> 0,0±0,3</td>

Table 31. Compound of Example 79, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td colspan="6">ΔΙΟΡ (mm Hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> 0,3±0,9</td><td> -3,9±0,5</td><td> -5,4±0,7</td><td> -5,8±0,8</td><td> -4,8±0,7</td><td> -2,8±1,0</td>

<td>Checklist Group</td><td> 0,0±0,2</td><td> 0,5±0,5</td><td> -0,5±0,4</td><td> -0,1±0,2</td><td> 0,5±0,4</td><td> 1,0±0,5</td>

Table 32. Compound of Example 80, 0.03% Ophthalmic

Solution (n = 6)

<td></td><td>ΔΙΟΡ (mm</td><td colspan="5">hg)</td>

<td>Time (Hrs.)</td><td> 0,5</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>tested Group</td><td> -0,9±1,3</td><td> -5,0±1,0</td><td> -5,9±0,7</td><td> -4,9±0,5</td><td> -5,0±0,8</td><td> -1,8±0,8</td>

<td>Checklist Group</td><td> -0,5±0,7</td><td> -1,1±0,6</td><td> -1,6±0,8</td><td> -0,9±1,1</td><td> -0,6±1,0</td><td> 1,3±0,9</td>

217

On the basis of the compounds of the present invention tested from each of Examples 1-84 above, with the exception of the compounds of the invention described in Tables 16-32 above, in the same manner as above, it was observed that all compounds exhibit almost the same result indicated in Tables 16 -32.

From the result indicated in Tables 14-32, it is obvious that as shown in Tables 14 and 15, Control Compounds A and B did not show any significant reduction of intraocular pressure even in a 1% suspension, which was a relatively high concentration.

As shown in Tables 11-32, all tested compounds of the invention showed an intraocular pressure lowering effect. In particular, the compounds of the invention shown in Tables 19-32 at a lower concentration than CGS-21680 showed the same level of intraocular pressure lowering effect as CGS-21680, which were mentioned as having an intraocular pressure lowering effect (see Table 16).

In addition, the compounds of the invention shown in Tables 20-32 were soluble at a high concentration (0.3% - 1%) below the concentration used in the measurement study (0.01% -0.03%) without a solubilizing agent, so it seems that they are useful as an ophthalmic solution.

218