WO2010036910A1

WO2010036910A1 - Heart protection by administering an amp-activated protein kinase activator

Info

Publication number: WO2010036910A1
Application number: PCT/US2009/058405
Authority: WO
Inventors: Yoshikazu Ohta; Sarah S. Bacus; Scott A. Shell
Original assignee: Individual
Current assignee: Individual
Priority date: 2008-09-26
Filing date: 2009-09-25
Publication date: 2010-04-01
Anticipated expiration: 2011-03-26

Abstract

The present invention relates to a method to protect heart of a mammal by administering an AMP-activated protein kinase activator including its salt or prodrug to a mammal, a pharmaceutical composition containing at least the AMPK activator for heart protection, use of the AMPK activator for preparing the pharmaceutical composition for heart protection, a method to activate the AMPK by administering a compound having an activity of activating the AMPK including its salt or prodrug to a mammal, a pharmaceutical composition to activate the AMPK that includes at least the compound having an activity of activating the AMPK, and use of the compound having an activity of activating the AMPK for preparing the pharmaceutical composition.

Description

DESCRIPTION

HEART PROTECTION BY ADMINISTERING AN AMP-ACTIVATED PROTEIN

KINASE ACTIVATOR

5

TECHNICAL FIELD The present invention relates to protection of a mammal's heart with a Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by the formula:

o wherein W is C(R¹) or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the 5 heteroaryl group represented by A to form an optionally substituted ring structure, and

Y¹ is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-

(CM alkylene)-,

R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted o group bonded via a carbon atom or a sulfur atom, or

R and R², or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas

are excluded, and use of the Compound (T) for preparing a corresponding pharmaceutical composition. It also relates to activating the AMP-activated protein kinase, a corresponding 5 pharmaceutical composition, and use of a compound having properties of activating the

AMP-activated protein kinase for preparing a corresponding pharmaceutical composition.

BACKGROUND ART

The gene of cell growth factor and growth factor receptor is called a proto-oncogene and plays a key role in the pathology of human tumor. The epithelial cell growth factor receptor family i o (ErbB) includes EGFR, HER2, HER3 and HER4, which are type I receptor type tyrosine kinases. These ErbB family members express in various cell groups, and are deeply involved in the control of the growth and differentiation of cells and the control of suppression of cell death (apoptosis suppression). For example, high expression of EGFR and HER2, and homeostatic activation of receptors are empirically known to transform cells. is It is also known that high expression and simultaneous expression of each of these receptors are poor prognostic factors in various cancer patients.

These receptors are bound with many peptide ligands such as EGF, TGFα and the like, and binding of the ligand promotes homo- or heterodimerization of the receptors. This induces increase of kinase activity from self-phosphorylation or transphosphorylation of the receptors, and causes 0 activation of downstream signaling pathway (MAPK, Akt) via a protein bound with a particular phosphorylated tyrosine residue. This is the mechanism of the receptor activity of the above- mentioned cell growth, differentiation, cell death suppression and the like, which is considered to be responsible for the high expression of receptor in cancer and malignant degeneration of cancer due to topical increase in the ligand concentration. In recent years, clinical use of a humanized anti-HER2 antibody (Trastuzumab) against

HER2 highly expressing breast cancer, clinical trial of anti-EGFR antibody and clinical trials of several low molecular weight receptor enzyme inhibitors have demonstrated a potential of these drugs against HER2 or EGFR for therapeutic drugs for cancer. While these drugs show a tumor growth inhibitory action in clinical and non-clinical trials, they are known to induce inhibition of receptor enzyme activity and suppression of downstream signaling pathway. Therefore, a compound inhibiting EGFR or HER2 kinase, or inhibiting activation of EGFR or HER2 kinase is effective as a therapeutic drug for cancer.

As a compound that inhibits receptor type tyrosine kinases represented by HER2/EGFR kinase, fused heterocyclic compounds (e.g., WO97/13771, WO98/02437, WO00/44728), quinazoline derivatives (e.g., WO02/02552, WO01/98277, WO03/049740, WO03/050108), thienopyrimidine derivatives (e.g., WO03/053446), aromatic azole derivatives (e.g., WO98/03648, WO01/77107, WO03/031442) and the like are known.

As to pyrrolo[3,2-d]pyrimidine derivatives, the following compounds are known as compounds having a cell growth inhibitory activity (Khim.-Farm. Zh_L, 1982, 16, 1338-1343; Collect. Czech. Chem. Commun., 2003, 68, 779-791).

As a compound having a receptor type tyrosine kinase activity, the following pyrrolo[3,2- djpyrimidine derivative is known (WO96/40142, WO98/23613).

5 Furthermore, as to pyrazolo[4,3-d]pyrimidine derivatives, 3,5,7-trisubstituted pyrazolo[4,3- d]pyrimidine derivatives are known as compounds having a CDK inhibitory action, a cell growth inhibitory action and/or an apoptosis inducing action (EP-A- 1348707), and 3- isopropylpyrazolo[4,3-d]pyrimidine derivatives are known as compounds having a CDKl/ cyclin B inhibitory activity (Bioorganic & Medicinal Chemistry Letters, 2003, 13, 2989-2992). Furthermore, o synthesis of 3 -methylpyrazolo[4,3-d]pyrirnidine derivatives has been reported (The Journal of

Organic Chemistry, 1956, 21, 833-836).

However, compounds that induce inhibition of receptor enzyme activity and suppress the downstream signaling pathway may cause alterations in fatty acid metabolism and as a result, these compounds may cause organ toxicity. Especially, the heart, which generates a tremendous amount of ATP using fatty acid and/or glucose through oxidation in order to pump necessary blood throughout a body, is affected by the alterations in fatty acid metabolism, and as a result, these compounds may damage the heart of mammals. It is known that GW2974, a EGFR2/EGF tyrosine kinase hinhibitor, can activate an AMP- activated protein kinase and protect heart (PNAS, 2007, vol.104, no.25, 10607-10612, WO2007/101191).

5 SUMMARY OF INVENΗON

The present invention protects heart of mammals from damages casued by cardiotoxic materials such as anti-cancer drugs, particularly, compounds having kinase inhibitory activities. Such damages can include damages caused by other cardio toxic materials, free radicals, oxidation, specially, β-oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNFα, other i o cytokines, cardiomyopathy, ischemic injury(ischemia), hypoxia, obesity, lipidemia, low-density lipoprotein (LDL), other lipid accumulation, glucose deprivation, starvation, heart transplant, statins, HMG-CoA reductase inhibitors, and other stresses to the heart.

The present invention relates to a method to protect heart of a mammal by administering a compound having activation acitivites of AMP-activated protein kinase, its salt or prodrug to a 15 mammal, i.e., AMPK (5'-adenosine monophosphate-activated protein kinase) activator, a pharmaceutical composition that protects heart of a mammal containing such as an AMPK activator, use of the AMPK activator for preparing a pharmaceutical composition that protects heart of a mammal, a method to activate the AMPK by administering to a mammal a compound having activation activities of the AMPK including its salt and prodrug, a pharmaceutical composition to 0 activate the AMPK that includes at least one compound having activation activities of the AMPK, and use of the compound that activates the AMPK for preparing a pharmaceutical composition.

This heart protection in this invention includes not only prevention of damage to the heart of a mammal but also treatment of such damage that may have occurred in the heart. Accordingly, the present invention provides the following.

[1] A method for protecting heart of a mammal in need thereof, the method comprising administering to the mammal an effective amount of at least one of Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by the formula:

A is an optionally substituted aryl group or an optionally substituted heteroaryl group,

X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and

Y¹ is a single bond or an optionally substituted C^ alkylene or an optionally substituted -O-

(C^ alkylene)-,

R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R and R , or R and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas

are excluded.

[2] The method for protecting heart of a mammal in need thereof according to [1] above, which protects the heart from damages caused by a cardiotoxic material, free radicals, oxidation, β- 5 oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNFα, other cytokines, cardiomyopathy, ischemia, hypoxia, obesity, lipidemia, low-density lipoprotein (LDL), other lipid accumulation, glucose deprivation, starvation, heart transplant, statins, and HMG-CoA reductase inhibitors.

[3] The method for protecting heart of a mammal in need thereof according to [1] above, which i o protects the heart from damages caused by the cardiotoxic material.

[4] The method for protecting heart of a mammal in need thereof according to [1] above, which protects the heart from cardiomyopathy.

[5] The method for protecting heart of a mammal in need thereof according to [1] above, which protects the heart from ischemic injury. i 5 [6] The method for protecting heart of a mammal in need thereof according to [1 ] above, wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

,1a wherein R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,

R^ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R^la and R²³, or R^2a and R^3a are optionally bonded to form an optionally substituted ring structure,

R^3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

R^3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

[7] A method for protecting heart of a mammal, the method comprising administering to the mammal an effective amount of N-{2-[4-({3-chloro-4-[3- (trMuorome1hyl)phenoxy]phenyl}ammo)-5H-pvrrolo[3,2-d]pyrimidin-5-yl]e1hyl} methylbutanamide, a salt thereof, or a prodrug thereof.

[8] A pharmaceutical composition for protecting heart of a mammal in need thereof comprising at least one of Compound (T), a salt thereof, or a prodrug thereof in a therapeutically effective amount wherein the Compound (T) is represented by the formula:

wherein W is C(R¹) or N,

X¹ is -NR³-Y^!-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and

Y¹ is a single bond or an optionally substituted Cu alkylene or an optionally substituted -O-

(Ci_-4 alkylene)-,

R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or

are excluded. [9]The pharmaceutical composition for protecting heart of a mammal in need thereof according to [8] above, wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

wherein R^la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,

R ϊ2a is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R^laand R²⁸, or R²*¹ and R^3a are optionally bonded to form an optionally substituted ring structure,

R ,3a^a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

R >3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

[10] A pharmaceutical composition for protecting heart of a mammal in need thereof comprising N- {2-[4-({3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5- yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount. [11] A use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for protecting heart of a mammal in need thereof, wherein the

Compound (T) is represented by the formula:

5 wherein W is C(R¹) or N,

X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the i o heteroaryl group represented by A to form an optionally substituted ring structure, and

(CM alkylene)-,

R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogen atom or an optionally substituted 15 group bonded via a carbon atom or a sulfur atom, or

R¹ and R², or R² and R³ are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas

are excluded.

[12] The use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for protecting heart of a mammal in need thereof according to [11] above, wherein the at least one of Compound (X), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

R^2a is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R^la and R^₅ or R^ and R^3a are optionally bonded to form an optionally substituted ring structure,

R ^a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

[13] A use ofN-{2-[4-({3-chloro-4-[3-(trifluoromethyl) phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimiάm-5-yl]ethyl}-3-hydroxy-3-me1hylbutanamide, a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for protecting heart of a mammal in need thereof. [14] A method for activating an AMP-activated protein kinase, the method comprising administering to a mammal in need thereof an effective amount of at least one of Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by a formula:

wherein W is C(R¹) or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group,

X¹ is -NR³- Y¹-, -O, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y¹ is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-

(CM alkylene)-,

R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R¹ and R², or R² and R³ are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas

are excluded. [15] Hie method for activating an AMP-activated protein kinase according to [14] above, wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ta) is represented by a formula:

wherein R > la^a is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,

,2a

R is an optionally substituted group bonded via a carbon atom or a sulfur atom, or ι la^a a_.nd R >2a , or rR>2a 3a

R a . , nd R are optionally bonded to form an optionally substituted ring structure,

R ^a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof. [16] A method for activating an AMP-activated protein kinase, the method comprising administering to a mammal in need thereof an effective amount of N-{2-[4-({3-chloro-4-[3- (1rifluoromethyl)phenoxy]phenyl}amm^ methylbutanamide, a salt thereof, or a prodrug thereof.

[17] A pharmaceutical composition for activating an AMP-activated protein kinase comprising at least one of Compound (J), a salt thereof, or a prodrug thereof in a therapeutically effective amount, wherein the Compound (T) is represented by a formula:

wherein W is C(R¹) or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and

Y¹ is a single bond or an optionally substituted C_1-4 alkylene or an optionally substituted -O-

(C_1-4 alkylene)-,

are excluded.

[18] The pharmaceutical composition for activating an AMP-activated protein kinase according to [17] above, wherein the at least one of Compound (Y), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is i o represented by a formula:

15 R²*¹ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R^la and R²⁸, or R^ and R^3a are optionally bonded to form an optionally substituted ring structure, R^3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and 5 C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

[19] A pharmaceutical composition for activating an AMP-activated protein kinase comprising N- {2-[4-({3-cMoro-4-[3-(trifluorome&yl)ph yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount. i o [20] A use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for activating an AMP-activated protein kinase, wherein the

Compound (T) is represented by a formula:

wherein W is C(R¹) or N, is A is an optionally substituted aryl group or an optionally substituted heteroaryl group,

X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and 0 Y¹ is a single bond or an optionally substituted Cn alkylene or an optionally substituted -O- (Q-₄ alkylene)-,

R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or

are excluded. [21] The use of at least one of Compound (I), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for activating an AMP-activated protein kinase according to [20] above, wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

, 1a wherein R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, R²⁸ is an optionally substituted group bonded via a carbon atom or a sul&r atom, or

R^la and R²³, or R²⁸ and R^3a are optionally bonded to form an optionally substituted ring

structure,

R ^a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

5 R^3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an

optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-I8 aryl group, or a salt thereof.

[22] A use ofN-{2-[4-({3-chloro-4-[3-(trrfluoromethyl) phenoxy]phenyl}arnino)-5H-pyrrolo[3,2-

i o d]pyrimidm-5-yl]ethyl}-3-hydroxy-3-me1hylbutanamide, a salt thereof, or a prodrug thereof for

preparing a pharmaceutical composition for activating an AMP-activated protein kinase.

BRIEF DESCRIPTION OF FIGURES

Figure 1 shows photographs of Human primary miocardiocytes treated with the compound

15 of the present invention and a comparative compound and blotted using various antibodies.

Figure 2 shows photographs of Human primary miocardiocytes treated with the compound of the present invention and comparative compounds and blotted using various antibodies.

Figure 3 shows photographs of Human primary miocardiocytes treated with the compound of the present invention and comparative compounds and blotted using various antibodies. 0 Figure 4 shows photographs of Human cardiac miocardiocytes treated with the compound of the present invention and comparative compounds in vitro, and lipids in the cells are stained.

Figure 5 shows photographs of rat cardiac miocardiocytes treated with the compound of the present invention and a comparative compound in vivo and blotted with various antibodies.

Figure 6 shows photographs of rat cardiac miocardiocytes treated with the compound of the 5 present invention and comparative compounds in vivo, and lipids in the cells are stained. DISCLOSURE OF THE INVENTION

Many new anti-cancer drugs having kinase inhibitory activities are accompanied by toxicity, especially cardiotoxicity. The present invention protects the heart of mammals from damage by using compounds having kinase inhibitory activities, especially, compounds having tyrosine kinase 5 inhibitory activities, and more specifically, compounds having EGFR/ HER2 (which is also referred to as ErbB2) tyrosine kinase inhibitory activities.

Cells of the myocardium of a mammal have the ability to regulate metabolism and control uptake and production of energy sources such as glucose and fatty acid. Compounds that induce inhibition of receptor enzyme activity and suppress the downstream signaling pathway often show o cardiotoxicity. The inhibition of phosphorylation in the signaling pathway affects that signaling pathway and causes alterations in fatty acid metabolism, which may lead to organ toxicity, including cardiotoxicity. The alterations in fatty acid metabolism are not only caused by the cardio- toxic materials but also caused by free radicals, oxidation, specially, β-oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNFα , other cytokines, ischemia, hypoxia,5 obesity, lipidemia, other lipid accumulation, glucose deprivation, starvation, low-density lipoprotein (LDL), heart transplant, statins, and HMG-CoA reductase inhibitors.

The AMP activated protein kinase (AMPK) is known as an enzyme that promotes phosphorylation reactions in downstream and inactivates acetyl-CoA carboxylase (ACC) and 3- hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGR). Therefore, it is thought o that the activated AMPK switches cardiac cells from a state of consuming ATP and synthesizing fatty acid, cholesterol, and protein, etc. to a state of producing ATP and oxidizing fatty acid, i.e., consuming fatty acid and prevents cardiotoxic damages from a mammal. In addition, it is known that the activity of the AMPK is significantly increased at the end of ischemia, and remains elevated throughout reperfusion.

The present inventors have conducted intensive studies and found that the heart of mammals can be protected with an AMP-activated protein kinase (AMPK) activator, a salt thereof, or a prodrug thereof.

The method for heart protection in this invention is to protect the heart of a mammal by administering at least a compound that is an AMPK activator, a salt thereof, or a prodrug thereof to a mammal. The invention also is directed to a heart protecting pharmaceutical composition that includes at least an AMPK activator, a salt thereof, or a prodrug thereof that can be administered to a mammal to protect the heart of the mammal and to the use of the AMPK activator, a salt thereof, or a prodrug thereof for the preparation of the pharmaceutical composition. Such pharmaceutical composition may contain other active ingredients, for example, hormonal therapeutic agents, anticancer agents, anthracyclines, anti-depressants, calcium channel blockers, beta-blockers, and the like. The AMPK activator, a salt thereof, or a prodrug thereof may be administered to a mammal to protect the heart in combination with drugs including the other active ingredients as listed above and/or other drugs than those including the ingredients listed above, simultaneously or separately, and non-drug therapies can be combined with administring the AMPK activator, a salt thereof, or a prodrug thereof.

The heart protection in this invention protects the heart of mammals from damage to the heart such as damages caused by cardiotoxic materials, cardiomyopathy, ischemic injury, hypoxia, glucose deprivation, starvation, and the like. This protection includes not only prevention of damage to the heart of a mammal, but also treatment of such damage that may have occurred in the heart. The AMPK activator may be the AMPK activator compound itself, salt thereof, or a prodrug thereof. The AMPK activator is preferably at least one of a tyrosine kinase inhibitor, a serine kinase inhibitor, threonine kinase inhibitor, salt thereof, and a prodrug thereof. The tyrosine kinase inhibitor may be an ErbB 1 and ErbB2 tyrosine kinase inhibitor, salt thereof, or a prodrug thereof.

Examples of compounds that are the AMPK activator and can be administered to a mammal to protect the heart in this method may be represented by the following formula (T) [1], a salt thereof, or a prodrug thereof [2] (sometimes collectively to be referred to as compound (I) in the present specification) as described in WO 2005-118588 and US 7,507,740:

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X¹ is -NFΛY¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and

Y¹ is a single bond or an optionally substituted C^alkylene or an optionally substituted -0-(CM alkylene)-, R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R¹ and R², or R² and R³ are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas

The compound (T) may be [3] the compound of the above-mentioned compound (T) [1], wherein W is C(R¹),

[4] a compound of the above-mentioned [3], wherein A is an aryl group substituted by a group of the formula -Y²-B and optionally further substituted, wherein Y² is a single bond, o -O-, -0-(C_1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, aureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-Cw alkyl- carbonyl group, each of which is optionally substituted,

[5] the compound of the above-mentioned [3], wherein R is a group of the formula -X -R wherein X² is a single bond, -NH- or -O-, and R⁴ is a hydrogen atom, a cyano group, or a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Cw alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-Cw alkyl-carbonyl group, a heterocyclic group, aheterocycle-Cw alkyl group, a heterocycle-carbonyl group or a heterocycle-Cw alkyl-carbonyl group, each of which is optionally substituted,

[6] a compound of the above-mentioned [3], wherein R² is a hydrogen atom or a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-C^ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C^ alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C_M alkyl group, aheterocycle-carbonyl group or aheterocycle- 5 CM alkyl-carbonyl group, each of which is optionally substituted, [7] a compound of the above-mentioned [3], wherein X is -NR³- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group,

[8] a compound of the above-mentioned [3], wherein A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, wherein Y is a single bond, i o -O-, -0-(C_1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-C_1-4 alkyl- carbonyl group, each of which is optionally substituted; R¹ is a group of the formula -X²-R wherein X² is a single bond, -NH- or -O-, and R⁴ is a- hydrogen atom, a cyano group, or a C_1-8 alkyl group, a C_2-8 alkenyl group, a

15 C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-C^ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-Cw alkyl-carbonyl group, a heterocyclic group, aheterocycle-C^ alkyl group, aheterocycle-carbonyl group or a heterocycle-Ci₄ alkyl-carbonyl group, each of which is optionally substituted; R² is a hydrogen atom or a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl 0 group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a

C_6-18 aryl group, a C_6-18 aryl-Cw alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C^ alkyl- carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-Ci-₄ alkyl group, a heterocycle-carbonyl group or a heterocycle-C^ alkyl-carbonyl group, each of which is optionally substituted; and

X is -NR - wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group,

[9] a compound of the compound (T) [1], wherein W is N,

[10] a compound of the above-mentioned [9], wherein A is an aryl group substituted by a 5 group of the formula -Y -B and optionally further substituted, wherein Y is a single bond,

-O-, -0-(C_1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-C^ alkyl- carbonyl group, each of which is optionally substituted,

[11] a compound of the above-mentioned [9], wherein R is a hydrogen atom or a C_1-8 alkyl i o group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Cw alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-Cw alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C^ alkyl group, aheterocycle-carbonyl group or aheterocycle- C_1-4 alkyl-carbonyl group, each of which is optionally substituted, 15 [12] a compound of the above-mentioned [9], wherein X¹ is

-NR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group,

[13] a compound of the above-mentioned [9], wherein X is

-NR - wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group; A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, 0 wherein Y² is a single bond, -O-, -0-(C_1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-C^ alkyl-carbonyl group, each of which is optionally substituted;

R is a hydrogen atom or a Ci_-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Q.₄ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-Cw alkyl- carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-Cw alkyl group, a heterocycle-carbonyl group or aheterocycle-C^ alkyl-carbonyl group, each of which is optionally substituted,

[14] a compound of the above-mentioned [9], wherein X is -NR³-;

A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, wherein Y² is a single bond, -O-, -0-(C_1-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-C^ alkyl-carbonyl group, each of which is optionally substituted; and R and R are bonded to form an optionally substituted ring structure,

[15] a compound of the compound (T) [1], wherein A is a C_6-18 aryl group substituted by substituent(s) selected from (i) a phenyloxy group optionally substituted by 1 to 5 substituents selected from

(a) halogen,

(b) optionally halogenated CM alkyl,

(c) hydroxy-Cw alkyl,

(d) heterocycle-C^ alkyl (preferably, 5- to 8-membered heterocycle-Q-₄ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),

(e) optionally halogenated C_1-4 alkyloxy,

(f) Cj₄ alkyl-carbonyl, (g) cyano,

(h) carbamoyl optionally substituted by C_1-8 alkyl, and (i) CM alkoxy-carbonyl,

(ii) aphenyl-C_1-3 alkyloxy group optionally substituted by 1 to 5 substituents selected from (a) halogen,

(b) optionally halogenated CM alkyl,

(c) hydroxy-Cw alkyl,

(d) heterocycle-C_M alkyl (preferably, 5- to 8-membered heterocycle-Cn alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),

(e) optionally halogenated CM alkyloxy,

(f) CM alkyl-carbonyl,

(g) cyano,

(h) carbamoyl optionally substituted by C_1-8 alkyl, and (i) C_1-4 alkoxy-carbonyl,

(iii) a 5- to 8-membered heterocycleoxy group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by 1 to 5 substituents selected from

(a) halogen, (b) optionally halogenated CM alkyl,

(c) hydroxy-Ci-4 alkyl,

(d) heterocycle-C_M alkyl (preferably, 5- to 8-membered heterocycle-C^ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),

(e) optionally halogenated Q₄ alkyloxy,

(f) CM alkyl-carbonyl,

(g) cyano, (h) carbamoyl optionally substituted by C_1-8 alkyl, and (i) CM alkoxy-carbonyl, and

(iv) 5- to 8-membered heterocycle-C_1-3 alkyloxy containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by 1 to 5 substituents selected from (a) halogen,

(b) optionally halogenated CM alkyl,

(c) hydroxy-Ci4 alkyl,

(d) heterocycle-Ci₄ alkyl (preferably, 5- to 8-membered heterocycle-C^ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),

(e) optionally halogenated Q₄ alkyloxy,

(f) CM alkyl-carbonyl,

(g) cyano,

(h) carbamoyl optionally substituted by C_1-8 alkyl, and (i) C^ alkoxy-carbonyl; wherein the C_6-18 aryl group is optionally further substituted by 1 to 4 substituents selected from halogen, Cμ alkyl, hydroxy-C^ alkyl and Cμ alkyloxy;

R¹ is (i) a hydrogen atom, (ii) a cyano group, or

(iii) a C₁₄ alkyl group or a C₂₄ alkenyl group, each of which is optionally substituted by -NR⁸-CO- (CH₂VMl⁶R⁷ wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a CM alkyl group, R is a hydrogen atom or a CM alkyl group, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-; R² is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) carboxy,

(c) cyano,

(d) optionally halogenated C₁₄ alkyloxy, (e) -O-(CH₂)_n-OH,

(f) -O-(CH₂)_n-O-CO-NH₂, (g) -O-(CH₂)_n-O-(optionaUy halogenated CM alkyl), (h) -O-(CH₂)_n-SO₂-(oρtionally halogenated C₁₄ alkyl), Ci) -O-(CH₂VSO₂-C_6-1S aTyI, (J) -O-(CH₂VSO₂-(CH₂VOH, (k) -O-(CH₂)_n-NR⁸-CO-C₁₄ alkyl, (1) -O-(CH₂VNR⁸-CO-(CH₂VSO₂-C_M alkyl,

(m) -O-(CH₂VNR⁸-Sθ₂-(optionalry halogenated C₁₄ alkyl), (n) -CO-NR⁸-(CH₂)_n-OH,

(o) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(p) -CO-NR⁸-O-C₁₄ alkyl,

Cq) -NR⁶R⁷, (r) -NR⁸-(CH₂VOH,

(s)

alkyl,

(t) -NR⁸-CO-(optionally halogenated C₁₄ alkyl),

(u) -NR⁸-CO-(CH₂)_n-OH,

(v) -NR⁸-CO-(CH₂)_n-CN, (W) -NR^CO-(CH₂VNR⁶R⁷,

(x) -NR⁸-CO-(CH₂VO-C_M alkyl,

(y) -NR⁸-CO-(CH₂)n-SO-(optionally halogenated C_M alkyl),

(z) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(aa) -NR⁸-CO-(CH₂VSO₂-C_3-8 cycloalkyl, (bb) -NR⁸-CO-(CH₂)_n-NR⁸-SO₂-C₁₄ alkyl,

(cc) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(ee) -NR⁸-CO-NH-O-C₁₄ alkyl,

(fit) -NR⁸-CO-NH-(CH₂)_n-O-C₁₄ alkyl, (gg) -NR⁸-C(-NH)-NH-C₁₄ alkyl,

(hh) -NR⁸-SO₂-(CH₂VSO₂-Ci₄ alkyl,

(U) -S-(CH₂VOH,

(D) -SO-(CH₂VOH, (kk) -SO₂-(CH₂VOH, and

(11) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-CM alkyl, - CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl,

-CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R is a hydrogen atom or a C₁₄ alkyl group, (CH₂)_n is optionally substituted by halogenated C₁₄ alkyl or hydroxy, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-; R is a hydrogen atom or a Cw alkyl group; or, R and R² are optionally bonded to form

R and R are optionally bonded to form C₂₄ alkylene optionally substituted by an imino group.

Particularly preferably, R is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group (particularly C_1-8 alkyl group), each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) carboxy, (c) cyano,

(d) optionally halogenated C₁₄ alkyloxy, (e) -O-(CH₂)_n-OH (wherein (CHa)_n is optionally substituted by hydroxy),

(f) -O-(CH₂)_n-O-CO-NH₂,

(g) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl), (h) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), (i) -0-(CH₂VSO₂-C_6-18 aryl,

O) -0-(CH₂VSO₂-(CH₂VOH,

(k) -O-(CH₂)_n-NR⁸-CO-C₁₄ alkyl,

(1) -O-(CH₂VNR⁸-CO-(CH₂VSO₂-C₁₄ alkyl,

(m) -O-(CH₂)_n-NR⁸-SO₂-(optionalry halogenated C₁₄ alkyl), (n) -CO-NR⁸-(CH₂VOH,

(o) -CO-NR⁸-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl),

(p) -CO-NR⁸-O-C₁₄ alkyl,

(Ci) -NR⁶R⁷,

(r) -NR⁸-(CH₂)_n-OH, (s) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl,

(t) -NR⁸-CO-(optk>nally halogenated C₁₄ alkyl),

(u) -NR -C0-(CH₂)_n-0H (wherein (CH₂)n is optionally substituted by optionally halogenated C₁₄ alkyl or hydroxy), (v) -NR⁸-CO-(CH₂VCN, (w) -NR⁸-CO-(CH₂)_n-NR⁶R⁷ (when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-), (x) -NR⁸-CO-(CH₂VO-C₁₄ alkyl,

(y) -NR⁸-CO-(CH₂VSO-(optionalry halogenated C₁₄ alkyl), (z) -JNR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(aa) -NR⁸-CO-(CH₂)_n-SO₂-C₃-₈ cycloalkyl,

(bb) -NR⁸-CO-(CH₂)_n-NR⁸-SO₂-C₁₄ alkyl, 5 (cc) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(ee) -NR⁸-CO-NH-O-C₁₄ alkyl,

(fi) -NR^CO-NH-(CH₂VO-C₁₄ alkyl,

(gg) -NR⁸-C(=NH)-NH-C₁₄ alkyl, i o (hh) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(ii) -S-(CH₂)_n-OH,

(ϋ) -SO-(CH₂)_n-OH,

(Mc) -SO₂-(CH₂VOH, and

(11) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- 5 to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl,

-CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), 0 wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, and R⁸ is a hydrogen atom or a C₁₄ alkyl group, [16] a compound of the compound (I) [1], wherein

A is a C_6-18 aryl group substituted by substituent(s) selected from (i) aphenyloxy group substituted by 1 to 5 substituents selected from

(a) halogen,

(b) optionally halogenated CH alkyl,

(c) hydroxy-Cn alkyl,

5 (d) heterocycle-Cn alkyl (preferably, 5- to 8-membered heterocycle-Cπ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),

(e) optionally halogenated CH alkyloxy,

(f) cyano, i o (g) carbamoyl optionally substituted by C_1-8 alkyl, and (h) CH alkoxy-carbonyl, (ii) a phenyl-Q-₃ alkyloxy group substituted by 1 to 5 substituents selected from

(a) halogen,

(b) optionally halogenated CH alkyl, 15 (c) hydroxy-Cπ alkyl,

(d) heterocycle-Cπ alkyl (preferably, 5- to 8-membered heterocycle-Cπ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),

(e) optionally halogenated CH alkyloxy, 0 (f) cyano,

(g) carbamoyl optionally substituted by C_1-8 alkyl, and (h) CH alkoxy-carbonyl,

(ϋi) a 5- to 8-membered heterocycleoxy group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is substituted by 1 to 5 substituents selected from

(a) halogen,

(b) optionally halogenated Q₄ alkyl, (c) hydroxy-Cw alkyl,

(d) heterocycle-C^ alkyl (preferably, 5- to 8-membered heterocycle-Cw alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),

(e) optionally halogenated Cμ alkyloxy, (f) cyano,

(g) carbamoyl optionally substituted by C_1-8 alkyl, and (K) C_\4 alkoxy-carbonyl, and

(iv) 5- to 8-membered heterocycle-C_1-3 alkyloxy containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is substituted by 1 to 5 substituents selected from

(a) halogen,

(b) optionally halogenated CM alkyl,

(c) hydroxy-C^ alkyl,

(d) heterocycle-C_M alkyl (preferably, 5- to 8-membered heterocycle-C^ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),

(e) optionally halogenated Cu alkyloxy,

(f) cyano, (g) carbamoyl optionally substituted by C_1-8 alkyl, and Qx) C₁₄ alkoxy-carbonyl; wherein the C_6-18 aryl group is optionally further substituted by 1 to 4 substituents selected from halogen and optionally halogenated C₁₄ alkyl; R is a hydrogen atom;

R is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group, each of which is substituted by substituent(s) selected from

(a) hydroxy,

(b) optionally halogenated C₁₄ alkyloxy, (C) -O-(CH₂VOH,

(d) -0-(CH₂VO-CO-NH₂,

(e) -0-(CH₂)_n-0-C₁₄ alkyl,

(f) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(g) -0-(CH₂VSO₂-C₆-_I8 aryl, (h) -0-(CH₂VSO₂-(CH₂VOH,

(i) -O-(CH₂VNR⁸-SO₂-(optionaUy halogenated C₁₄ alkyl),

0) -CO-NR⁸-(CH₂)_n-OH,

(k) -CO-NR⁸-(CH₂VSO₂-(oρtionally halogenated C₁₄ alkyl),

(1) -NR⁶R⁷, (m) -NR⁸-(CH₂)_n-OH,

(n) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl,

(o) -NR⁸-CO-(CH₂)_n-OH,

(p) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl, (q) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl),

(r) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(s) -NR⁸-CO-(CH₂)_n-SO₂-C₃.₈ cycloalkyl,

(t) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl, 5 (u) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(v) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(W) -S-(CH₂VOH,

(X) -SO-(CH₂VOH,

(y) -SO₂-(CH₂VOH, and i o (z) -NR⁸-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), 15 wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R⁸ is a hydrogen atom or a C₁₄ alkyl group, and (CH₂)_n is optionally substituted by C₁₄ alkyl or hydroxy);

R³ is a hydrogen atom or a C_1-6 alkyl group; or,

R¹ and R² are optionally bonded to form

R and R are optionally bonded to form C₂₄ alkylene, particularly preferably, R² is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group (particularly, a C_1-8 alkyl group), each of which is substituted by substituent(s) selected from

(a) hydroxy,

(b) optionally halogenated CH- alkyloxy,

(c) -0-(CHa)_n-OH (wherein (CH₂)_H is optionally substituted by hydroxy), 5 (d) -0-(CH₂VO-CO-NH₂,

(e) -0-(CH₂)_n-0-Ci₄ alkyl,

(f) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(g) -0-(CH₂VSO₂-Cw₈ aryl,

(h) -0-(CH₂VSO₂-(CH₂VOH, i o (i) -O-(CH₂VNR⁸-SO₂-(optionally halogenated C₁₄ alkyl),

(j) -CO-NR⁸-(CH₂)_n-OH,

(k) -CO-NR⁸-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl),

(1) -NR⁶R⁷,

(m) -NR⁸-(CH₂VOH, is (n) -NR⁸-(CH₂VSO₂-C₁₄ alkyl,

(o) -NR⁸-CO-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(p) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(q) -NR⁸-CO-(CH₂VSO-(optionally halogenated C₁₄ alkyl),

(r) -NR⁸-CO-(CH₂)_n-SO₂-(oρtionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally 0 substituted by C₁₄ alkyl),

(s) -NR⁸-CO-(CH₂VSO₂-C₃.₈ cycloalkyl,

(t) -NR⁸-CO₂-(CH₂)_n-SO₂-Ci₄ alkyl,

(u) -NR⁸-CO~NH-(CH₂)_n-SO₂-C₁₄ alkyl, (v) -NR⁸-SO₂-(CH₂)n-Sθ2-C₁₄ alkyl, (w) -S-(CH₂VOH, (x) -SO-(CH₂)_n-OH, (y) -SO₂-(CH₂VOH, and

5 (z) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C_1-4 alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, - CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), i o wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, and R is a hydrogen atom or a C₁₄ alkyl group,

[17] a compound of the above-mentioned [16], wherein R² is (i) a C_5-8 alkyl group substituted by hydroxy, (ϋ) a C_1-8 alkyl group substituted by substituent(s) selected from

25 (a) halogenated C₁₄ alkyloxy, O) -O-(CH₂VOH,

(c) -0-(CH₂VO-CO-NH₂,

(d) -0-(CH₂VO-(optionally halogenated C₁₄ alkyl),

(e) -O-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl), 0 (f) -0-(CH₂VSO₂-C_6-18 aryl,

(g) -O-(CH₂VNR⁸-SO₂-(optionally halogenated C₁₄ alkyl), (h) -CO-NR⁸-(CH₂)_n-OH,

(i) -CO-NR⁸-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl), G) -NR⁸-(CH₂)_n-SO₂-Ci4 alkyl, (k) -NR⁸-CO-(CH₂)_n-OH, (1) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(m) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl), (n) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(0) -NR⁸-CO-(CH₂)_n-SO₂-C₃-8 cycloalkyl, (p) -NR⁸-CO₂-(CH₂)_n-SO₂-Ci₄ alkyl,

(q) -NR⁸-CO-NH-(CH₂)n-SO₂-C₁₄ alkyl,

(r) -NR⁸-SO₂-(CH₂VSO₂-C₁₄ alkyl, (s) -S-(CH₂)_n-OH,

(t) -SO-(CH₂VOH,

(u) -SO₂-(CH₂VOH, and

(v) -NR⁸-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R⁸ is a hydrogen atom or a C₁₄ alkyl group, and (CH₂)_n is optionally substituted by C₁₄ alkyl, (in) a C₂-₈ alkenyl group optionally substituted by hydroxy, or

(iv) a C_2-S alkynyl group optionally substituted by hydroxy, particularly preferably, R is

(1) a C₅-_S alkyl group substituted by hydroxy, (ii) a C_1-8 alkyl group substituted by substituent(s) selected from

(a) halogenated C₁₄ alkyloxy,

(b) -O-(CH₂)n-OH (wherein (CH₂)_n is optionally substituted by hydroxy),

(c) -0-(CH₂VO-CO-NH₂, (d) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl),

(e) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(f) -0-(CH₂VSO₂-C_6-I8 aryl,

(g) -0-(CH₂)n-NR⁸-S0₂-(optionally halogenated C₁₄ alkyl), (h) -CO-NR⁸-(CH₂)_n-OH, (i) -CO-NR⁸-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl),

O) -NR⁸-(CH₂)_n-S0₂-C₁₄ alkyl,

(k) -NR⁸-CO-(CH₂VOH (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(1) -NR⁸-CO-(CH₂VO-C₁₄ alkyl,

(m) -NR⁸-CO-(CH₂VSO-(optionally halogenated C₁₄ alkyl), (n) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(o) -NR⁸-CO-(CH₂VSO₂-C_3-8 cycloalkyl,

(p) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(q) -NR⁸-CO-NH-(CH₂VSO₂-C₁₄ alkyl, (r) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(S) -S-(CH₂VOH,

(t) -SO-(CH₂VOH,

(u) -SO₂-(CH₂VOH, and (v) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized CM alkylthio, -CO-CM alkyl, - CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₄ alkyl group,

(iϋ) a C₂-S alkenyl group optionally substituted by hydroxy, or

(iv) a C_2-8 alkynyl group optionally substituted by hydroxy,

[18] a compound of the compound (T) [1], which is selected from the following (A) to (H): (A) a compound (T) wherein

W is CR¹;

A is a phenyloxy-C_6-18 aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from

(i) halogen, (ii) optionally halogenated C₁₄ alkyl,

(iii) hydroxy-C₁₄ alkyl,

(iv) heterocycle-C₁₄ alkyl (preferably, 5- to 8-membered heterocycle-C₁₄ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated C₁₄ alkyloxy,

(vi) C₁₄ alkyl-carbonyl,

(vii) cyano,

(viii) carbamoyl optionally substituted by C_1-8 alkyl, and (ix) C₁₄ alkoxy-carbonyl, and the C_6-18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen,

C₁₄ alkyl, hydroxy-C^ alkyl, C_1-4 alkyloxy, carboxy and C₁₄ alkoxy-carbonyl;

X is -NR³ - wherein R³ is a hydrogen atom or a Cw alkyl group;

5 R¹ IS

(i) a hydrogen atom,

(ii) a cyano group, or

(iϋ) a CM alkyl group or a C₂₄ alkenyl group, each of which is optionally substituted by -NR⁸-CO-

(CH₂VNR⁶R⁷ o wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R is a hydrogen atom or a CM alkyl group, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-; and

R² is (i) a hydrogen atom or

(ii) a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) carboxy,

(c) cyano,

(d) optionally halogenated C₁₄ alkyloxy, (e) -O-(CH₂)_n-OH,

(f) -0-(CH₂VO-CO-NH₂,

(g) -O-(CH₂)n-O-(optionally halogenated CM alkyl),

(h) -O-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl), (i) -0-(CBb)_n-SQ₂-C₆-_I8 aryl,

(j) -O-(CH₂)_n-SO₂-(CH₂)_n-OH,

(k) ~O-(CH₂)_n-NR⁸-CO-C_M alkyl,

(1) -O-(CH₂)_n-Ml⁸-CO-(CH₂)_n-SO₂-C₁₄ alkyl, (m) -O-(CH₂)_n-NR⁸-SO₂-(optionally halogenated C₁₄ alkyl),

(n) ~CO-NR⁸-(CH₂)_n-OH,

(o) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(p) -CO-NR⁸-O-C₁₄ alkyl,

(r) -NR⁸-(CH₂)_n-OH,

(s) ~NR⁸-(CH₂VSO₂-C₁₄ alkyl,

(t) -NR⁸-CO-(optionally halogenated C₁₄ alkyl),

(u) -NR⁸-CO-(CH₂)_n-OH,

(v) -NR⁸-CO-(CH₂)_n-CN, (w) -M^-CO-tCH^_n-Ml'k⁷,

(x) -NR⁸-CO-(CH₂)_n-O-Ci₄ alkyl,

(y) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl),

(z) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(aa) -NR⁸-CO-(CH₂)_n-SO₂-C₃-8 cycloalkyl, (bb) -NR⁸-CO-(CH₂)_n-NR⁸-SO₂-C₁₄ alkyl,

(cc) -NR⁸-CO₂-(CH₂)_n-SO₂-Ci₄ alkyl,

(dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(ee) -NR⁸-C0-NH-0-C₁₄ alkyl, (S) -NR⁸-CO-NH-(CH₂)_n-O-C₁₄ alkyl,

(gg) -NR⁸-C(=NH)-NH-C₁₄ alkyl,

(hh) -NR⁸-SO₂-(CH₂VSO₂-C₁₄ alkyl,

(ϋ) -S-(CH₂)_n-OH, 5 (U) -SO-(CH₂VOH,

(kk) -SO₂-(CH₂VOH, and

(11) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by i o substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl,

-CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R⁸ is a hydrogen atom or a C₁₄ alkyl group, (CH₂)_n is optionally substituted by 15 optionally halogenated C₁₄ alkyl or hydroxy, and when n is not less than 2, a subset -CH₂CH₂- of

(CH₂)_n is optionally replaced by -CH=CH-; or

R and R are optionally bonded to form

R and R are optionally bonded to form C₂₄ alkylene optionally substituted by an imino group, 0 particularly preferably, R^ is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group (particularly, C_1-8 alkyl group), each of which is optionally substituted by substituent(s) selected (a) hydroxy,

(b) carboxy,

(c) cyano,

(d) optionally halogenated C₁₄ alkyloxy, (e) -0-(CH₂VOH (wherein (CHz)_n is optionally substituted by hydroxy),

(f) -O-(CH₂)_n-O-CO-NH₂,

(g) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl),

(h) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(i) -0-(CH₂VSO₂-C_6-18 aryl, G) -O-(CH₂VSO₂-(CH₂VOH,

(k) -O-(CH₂VNR⁸-CO-C_M alkyl,

(1) -O-(CH₂VNR⁸-CO-(CH₂)_n-SO₂-C_M alkyl,

(m) -O-(CH₂)n-NR⁸-SO₂-(optionalry halogenated C₁₄ alkyl),

(n) -CO-NR⁸-(CH₂)_n-OH, (o) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(p) -CO-NR⁸-O-C₁₄ alkyl,

(Cj) -NR⁶R⁷,

(r) -NR⁸-(CH₂)_n-OH,

(s) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl, (t) -NR⁸-CO-(optionally halogenated C₁₄ alkyl),

(u) -NR -CO-(CH₂VOH (wherein (CH₂)n is optionally substituted by optionally halogenated C₁₄ alkyl or hydroxy),

(v) -NR⁸-CO-(CH₂)n-CN, (w) -NR^CO-(CH₂VNR⁶R⁷ (when n is not less than 2, a subset

-CH₂CH₂- of (CH₂)n is optionally replaced by -CH=CH-),

(x) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(y) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl), 5 (z) -NR⁸-CO~(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(aa) -NR⁸-CO-(CH₂)_n-SO₂-C₃-₈ cycloalkyl,

(bb) -NR⁸-CO-(CH₂)_n-NR⁸-SO₂-C₁₄ alkyl,

(cc) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl, i o (dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(ee) -NR⁸-C0-NH-0-C₁₄ alkyl,

(ft) -NR⁸-CO-NH-(CH₂)_n-O-C₁₄ alkyl,

(gg) -NR⁸-C(=NH)-NH-C₁₄ alkyl,

(hh) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl, is (U) -S-(CH₂VOH,

Qi) -SO-(CH₂VOH,

(kk) -SO₂-(CH₂VOH, and

(11) -NR⁸-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an 0 oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl,

-CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a CM alkyl group, and R⁸ is a hydrogen atom or a CM alkyl group, (B) a compound (T) wherein W is CR¹; A is phenyl-C_1-3 εύkyhxy-Cβ-is aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C₁₄ alkyl and cyano, and the C_6-18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen, CM alkyl optionally having hydroxy and CM alkyloxy; X¹ is -NR³ - wherein R is a hydrogen atom or a C_1-6 alkyl group; R¹ is (i) a hydrogen atom,

(ii) a C₁₄ alkyl group or a C₂₄ alkenyl group, each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) amino, (C) -M^-CO-(CH₂VNR⁶R⁷, and

(d) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R⁸ is a hydrogen atom or a C₁₄ alkyl group, and when n is not less than 2, a subset -CH₂-CH₂ of (CH₂)_n is optionally replaced by -CH=CH-, or (ϋi) a C_6-18 aryl group optionally substituted by substituent(s) selected from

(a) amino,

(b) carboxy, and

(c) -NR⁸-CO-(CH₂)_n-O-Ci₄ alkyl wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a Q₄ alkyl group, or (iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and R² is (i) a hydrogen atom, (ϋ) a C_1-8 aUkyl group optionally substituted by substituent(s) selected from

(a) halogen,

(b) hydroxy,

(c) Q₄ alkyloxy, (d) -O-(CH₂)_n-OH, (e) -O-(CH₂)_n-O-C_M alkyl,

(f) -CO-NR⁸-(CH₂)_n-OH,

(g) -NR⁶R⁷, and

(h) -NR⁸-(CH₂)_n-OH wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a CM alkyl group, and R⁸ is a hydrogen atom or a Cw alkyl group,

(in) a C_6-18 aryl-C_M alkyl group optionally substituted by substituent(s) selected from

(a) CM alkyl optionally having hydroxy,

(b) carboxy,

(c) CM alkoxy-carbonyl, (d) 5- to 8-membered heterocycle-carbonyl having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which optionally has substituent(s) selected from hydroxy and C_1-4 alkyl, and

(e) C₁^ alkyl-carbarnoyl optionally having substituent(s) selected from hydroxy and carbamoyl, (iv) a C_6-18 aryl-carbonyl group optionally substituted by C₁₄ alkoxy, (v) a C_6-18 aryl-sulfonyl group optionally substituted by C₁₄ alkoxy, or (vi) a 5- to 8-membered heterocycle-C₁₄ alkyl group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by substituent(s) selected from

(a) carboxy, and

(b) C₁₄ alkoxy-carbonyl; or

R and R are optionally bonded to form C₂₄ alkylene,

(C) a compound (T) wherein W is CR¹; A is a 5- to 8-membered heterocycleoxy-C₆-₁₈ aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, wherein the heterocycleoxy moiety is optionally substituted by 1 to 5 substituents selected from

(i) halogen,

(ii) C₁₄ alkyl, (iϋ) C₁₄ alkyl-carbonyl,

(iv) optionally halogenated C₁₄ alkoxy-carbonyl,

(v) C_3-8 cycloalkyl-carbonyl, and

(vi) a carbamoyl group optionally substituted by substituent(s) selected from

(a) optionally halogenated C_1-8 alkyl, (b) C_3-8 cycloalkyl, and

(c) C_6-18 aryl optionally substituted by substituent(s) selected from halogen, C₁₄ alkyl and C₁₄ alkyloxy, and the C₆.₁₈ aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and optionally halogenated C₁₄ alkyl;

X is -NR - wherein R is a hydrogen atom or a C₁^ alkyl group; R¹ is (i) a hydrogen atom,

(ii) a C₁₄ alkyl group or a C_2-4 alkenyl group, each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) amino,

and

(d) -NR⁸-CO-(CH₂yθ-C₁₄ alkyl, wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R is a hydrogen atom or a C₁₄ alkyl group, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-, (iii) a C_6-18 aryl group optionally substituted by substituent(s) selected from

(a) C₁₄ alkyl optionally substituted by substituent(s) selected from hydroxy, -NR -(CH₂)_n-SO₂-C₁₄ alkyl and -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(b) amino,

(c) C₁₄ alkyloxy,

(d) carboxy, and

(e) -NR^CO-(CH₂VO-C₁₄ alkyl, wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C₁₄ alkyl group, or

(iv) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and

R² is (i) a hydrogen atom, (ii) a C₁₄ alkyl group optionally substituted by substituent(s) selected from

(a) halogen,

(b) hydroxy,

(c) C_1-4 alkyloxy, 5 (d) carboxy,

(e) C₁₄ alkoxy-carbonyl,

(f) -O-(CH₂)_n-OH,

Cg) -O-(CH₂VO-C₁₄ alkyl,

(h) -CO-NR⁸-(CH₂)_n-OH, and i o (i) -NR⁸-CO-(CH₂)_n-Sθ₂-C₁₄ alkyl wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C₁₄ alkyl group, or

(iϋ) a C_6-18 aryl-C₁₄ alkyl group optionally substituted by C₁₄ alkyl optionally having hydroxy; or

R² and R are optionally bonded to form C₂₄ alkylene,

(D) a compound (T) wherein is W is CR¹;

A is 5- to 8-memberedheterocycle-C_1-3 alkyloxy-Ce-ϊs aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom wherein the C_6-18 aryl moiety is optionally further substituted by halogen;

X is -NR³ - wherein R is a hydrogen atom or a C_1-6 alkyl group; 0 R¹ is (i) a hydrogen atom or

(ii) a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom; and

R² is (i) a hydrogen atom, (ϋ) Ci₄ atkyl optionally substituted by substituent(s) selected from

(a) C₁-* alkyloxy,

(b) -O-(CH₂)_n-OH, and

(c) -NR⁸-CO-(CH₂)_n-SO₂-C₁₄ alkyl wherein n is an integer of 1 to 4, and R is a hydrogen atom or a CM alkyl group, or

(iϋ) a 5- to 8-membered heterocycle-C^ alkyl group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is optionally substituted by substituent(s) selected from

(a) carboxy, and (b) CM alkoxy-carbonyl,

(E) a compound (T) wherein

W is N;

A is a phenyloxy-C₆.₁₈ aryl group wherein the phenyloxy moiety is optionally substituted by 1 to 5 substituents selected from optionally halogenated CM alkyl and cyano, and the C_6-18 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and CM alkyl;

1 V ¹^*

X is -NR - wherein R is a hydrogen atom or a Cw alkyl group; and R² is (i) a hydrogen atom or

(ii) a CM alkyl group optionally substituted by -O-(CH₂)_n-OH wherein n is an integer of 1 to 4, (F) a compound (T) wherein W is N; A is a phenyl-C_1-3 alkyloxy-C_6-18 aryl group wherein the phenyl moiety is optionally substituted by 1 to 5 substituents selected from halogen and cyano, and the C₆₄8 aryl moiety is optionally further substituted by 1 to 4 substituents selected from halogen and C₁₄ alkyl;

X is -NR³ - wherein R³ is a hydrogen atom or a C₁^ alkyl group; and

R² is (i) a hydrogen atom, 5 (ii) a CM alkyl group optionally substituted by 1 to 5 substituents selected from the group consisting of

(a) hydroxy,

(b) -O-(CH₂)_n-OH,

(c) -NR⁸-(CH₂)_n-O-C_M alkyl, i o (d) -NR⁸-(CH₂)_n-heterocyclic group (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom), and

(e) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl wherein n is an integer of 1 to 4, and R⁸ is a hydrogen atom or a C₁₄ alkyl group, 15 (iii) a C_6-18 aryl group optionally substituted by C₁₄ alkyl optionally substituted by substituent(s) selected from hydroxy, -NR⁸-(CH₂)n-OH, -NR⁸-(CH₂)_n-heterocyclic group (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom) and -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl, or

(iv) a C_6-18 aryl-C₁₄ alkyl group optionally substituted by 1 to 5 substituents selected from the group 0 consisting of

(a) carboxy,

(b) C₁₄ alkoxy-carbonyl, and

(c) -CO-NR⁸-(CH₂)_n-O-C₁₄ alkyl wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C₁₄ alkyl group; or R² and R³ are optionally bonded to form C₂₄ alkylene, (G) a compound (J) wherein W is N; A is a 5- to 8-membered heterocycleoxy-C^s aryl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom wherein the heterocycleoxy moiety is optionally substituted by C₁₄ alkyl, and the C_6-18 aryl moiety is optionally further substituted by C₁₄ alkyl; X¹ is -NR³ - wherein R³ is a hydrogen atom or a C_1-6 alkyl group; and R is (i) a hydrogen atom,

(ϋ) a C₁₄ alkyl group optionally substituted by hydroxy,

(iϋ) a C_6-18 aryl group optionally substituted by substituent(s) selected from

(a) nitro,

(b) amino, (c) -CO-NR⁸-(CH₂)_n-O-C₁₄ alkyl,

(d) -NR⁸-CO-(CH₂VO-C₁₄ alkyl,

(f) -NR⁸~CO-(CH₂)n-COOH

(g) -NR⁸~CO-(CH₂)_n-CO₂-C₁₄ alkyl, and (h) -NR⁸-CO-(CH₂)_m-O-(CH₂)_n-O-C₁₄ alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, and R is a hydrogen atom or a C₁₄ alkyl group, or

(iv) a C_6-18 aryl-C₁₄ alkyl group optionally substituted by substituent(s) selected from (a) carboxy,

(b) CM alkoxy-carbonyl,

(c) -CO-NR⁸-(CH₂)_n-O-Ci4 alkyl, wherein n is an integer of 1 to 4, and R is a hydrogen atom or a CM alkyl group); or R and R are optionally bonded to form C₂₄ alkylene,

(H) a compound (I) wherein

W is CH;

A is a C_6-18 aryl group optionally substituted by substituent(s) selected from

(a) carboxy, (b) CM alkoxy-carbonyl,

(c) a 5- to 8-membered heterocycle-carbonyl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (preferably, a 5- to 8-membered cyclic amino- carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom), which is optionally substituted by C_6-18 aryl-C^ alkyl; (d) a carbamoyl group optionally substituted by C_6-18 aryl-Cw alkyl, and

(e) a ureido group optionally substituted by C_6-18 aryl-Q-4 alkyl;

X¹ is -NR³ - wherein R³ is a hydrogen atom or a C_1-6 alkyl group; and R² is a hydrogen atom, or

[19] a compound of the compound (T) [1], wherein A is (i) a C_6-1S aryl group or (if) a 5- to 8- membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom

(preferably, an oxygen atom, a sulfur atom and a nitrogen atom), each of which is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, C₁₄ alkyloxymethyl, hydroxy-C_M alkyl, C₁^ alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl- carbonylamino, Q₄ alkoxy-carbonylarnino, CM alkylsulfonylamino and a group of the formula - Y²-B, wherein Y² is a single bond, -O-, -0-(C_1-3 alkylene)-, -NH- or -S-, B is

(A) (i) a C_6-18 aryl group, (ϋ) a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group, (ϋi) a C_3-8 cycloalkyl group, (iv) a carbamoyl group, (v) a C_6-18 aryl-carbonyl group or (vi) a C_6-18 aryl-C^ alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated Q₄ alkyloxy, CM alkyloxymethyl, hydroxy-C^ alkyl, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM alkylsulfonylamino or

(B) a ureido group optionally having 1 or 2 C_1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the ureido group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituent(s) selected from substituent group T, wherein the substituent group T is a group consisting of

(a) halogen,

(b) oxo, (c) optionally halogenated C₁₄ alkyl, (d) -(CH₂)_m-Q,

(e) -(CH^Z^optionally halogenated C₁-₄ alkyl),

(f) -(CH₂)_m-Z¹-C₃_8 cycloalkyl, (g) -(CH₂)_m-Z²-(CH₂)_n-Q,

(h) -(CH₂)_m-Z²-(CH₂)_n-Z¹-(optionally halogenated C₁₄ alkyl),

(i) -(CHzVZ^CEbVZ¹-^ cycloalkyl,

Q) -(CH₂)_J11-Z¹ -(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom),

(k) -(CH₂)_m-Z²-C₁₄ alkoxy, and

(1) -(CR₂)_m-Z²-(C}i₂)a-Zⁱ-(CE₂\~Z^l-C_lA alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,

Q is hydroxy, carboxy, cyano, nitro, -NR⁶R⁷, -CONR⁶R⁷, -OCONH₂ or -SO₂NR⁶R⁷, Z¹ is -O-, -CO-, -C(OH)R⁸-, -C(=N-0R⁸)-, -S-, -SO-, -SO₂-,

-N(COR⁸)-, -N(CO₂R⁹)-, -N(SO₂R⁹)-, -CO-O-, -0-C0-, -CO-NR⁸-,

-NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH~, -NR⁸-SO₂-, or -NR⁸-C(=NH)-NH-,

Z² is -0-, -CO-, -C(OH)R⁸-, -C(-N-0R⁸)-, -S-, -SO-, -SO₂-, -NR⁸-, -N(COR⁸)-, -N(CO₂R⁹)-, -

N(SO₂R⁹)-, -CO-O-, -0-C0-, -CO-NR⁸-, -NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH-, -NR⁸-C(=NH)-NH-, -NR⁸-SO₂-, or -SO₂-NR⁸-,

(CH₂)_m and (CH₂)_n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C₁₄ alkyl and hydroxy, and when m or n is not less than 2, a subset -

CH₂CH₂- of (CH₂)Hi and (CH& is optionally replaced by -CH=CH- or -OC-, R and R are the same or different and each is a hydrogen atom or a CM alkyl group, or R and R form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, Cμ alkyloxyrnethyl, hydroxy CM alkyl, C_1-4 alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM alkylsulfonylamino, R is a hydrogen atom or CM alkyl, and R is CM alkyl, R³ is (i) a hydrogen atom, or (ii) a C_1-S alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group or a C_3-8 cycloalkyl group, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, CM alkyloxy, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM alkylsulfonylamino, or R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form a saturated or unsaturated 4- to 8-membered nitrogen-containing heterocycle, which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, CM alkyloxy, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM alkylsulfonylamino, Y¹ is (i) a single bond or (ii) CM alkylene or -0-(CM alkylene)-, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, CM alkyloxy, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM alkylsulfonylamino,

R¹ is (i) a hydrogen atom or (ϋ) a group represented by the formula -X -R , wherein X² is a single bond, -NH- or -O-, and R is (i) a hydrogen atom, (ii) a cyano group, (ϋi) a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a C_1-8 alkyl-carbonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Cn alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-Cw alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-memberedheteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group), a heterocycle-Ci-₄ alkyl group, aheterocycle-carbonyl group or aheterocycle-Q-₄ alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group T, or (iv) a carbamoyl group optionally having 1 or 2 C_1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituent(s) selected from substituent group T, R² is (i) a hydrogen atom, (ii) a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-C^ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C^ alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C^ alkyl group, aheterocycle-carbonyl group or aheterocycle- Cu alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected frorα substituent group T, or

(iϋ) a carbamoyl group optionally having 1 or 2 C_1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituent(s) selected from substituent group T, or R¹ and R², or R² and R³ are optionally bonded to form a saturated or unsaturated 4- to 8-membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group T.

The compound (I) that is an AMPK activator and to be at least one of compounds administered to a mammal to protect heart in this method may be a compound (Ia) represented by the following formula [20], a salt thereof, or a prodrug thereof [21] (sometimes collectively to be referred to as compound (fa) in the present specification):

wherein R ^a is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom,

R ^a is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R ^a and R²*¹, or R²*¹ and R^3a are optionally bonded to form an optionally substituted ring structure, R^3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R^3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B^a is an optionally substituted benzene ring, and C^a is an optionally substituted C_6-18 aryl group, 5 [22] a compound of the compound (Ta) [20], wherein

R²³Is

(i) a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Q-₄ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C^ alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a i o heterocyclic group, a heterocycle-Cw alkyl group, a heterocycle-carbonyl group or a heterocycle- Ci-₄ alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from the group (substituent group T) consisting of

(a) halogen,

(b) oxo,

15 (c) optionally halogenated CM alkyl, (d) -(CH₂)_m-Q,

(e) -(CH₂)_m~Z -(optionally halogenated C₁₄ alkyl),

(f)

cycloalkyl, (g) -(CH₂)_m-Z²-(CH₂)_n-Q, 0 (h) -(CH^m-Z^CH^n-Z^optionally halogenated C₁₄ alkyl), (i) -(CH₂)_m-Z²-(CH.₂VZ^l-C₃._s cycloalkyl, Q) -(CH^_m-Z^optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom),

(k) -(CH₂)_m-Z²-C_M alkoxy, and

wherein m is an integer of 0 to 4, n is an integer of 1 to 4,

Q is hydroxy, carboxy, cyano, nitro, -NR⁶R⁷, -CONR⁶R⁷, -OCONH₂ or -SO₂NR⁶R⁷,

Z¹ is -O-, -CO-, -C(OH)R⁸-, -C(=N-0R⁸)-, -S-, -SO-, -SO₂-,

-N(COR⁸)-, -N(CO₂R⁹)-, -N(SO₂R⁹)-, -CO-O-, -0-C0-, -CO-NR⁸-,

-NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH-, -NR⁸-SO₂-, or -NR⁸~C(=NH)-NH-, Z² is -0-, -CO-, -C(OH)R⁸-, -C(=N-0R⁸)-, -S-, -SO-, -SO₂-, -NR⁸-, -N(COR⁸)-, -N(CO₂R⁹)-, -

N(SO₂R⁹)-, -CO-O-, -0-C0-, -CO-NR⁸-,

-NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH-, -NR⁸-C(=NH)-NH-, -NR⁸-SO₂-, or -SO₂-NR⁸-,

(CH₂)_m and (CRi)_n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl and hydroxy, and when m or n is not less than 2, a subset - CH₂CH₂- of (CH₂)m and (CH₂) is optionally replaced by -CH=CH- or -OC-,

R⁶ and R⁷ are the same or different and each is a hydrogen atom or a CM alkyl group, or R⁶ and R⁷ are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group,

R⁸ is a hydrogen atom or a C_1-4 alkyl group, and R⁹ is a CM alkyl group, or

(ϋ) a carbamoyl group optionally having 1 or 2 C_1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein said carbamoyl group has two substituents, which optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group optionally substituted by substituent(s) selected from substituent group T, [23] a compound of the compound (Ia) [20], wherein

B^a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, C₁^ alkyl, hydroxy-Ci4 alkyl and Q₄ alkyloxy;

C^a is a phenyl group optionally substituted by 1 to 5 substituents selected from

(i) halogen,

(ϋ) optionally halogenated CM alkyl,

(iϋ) hydroxy-Cw alkyl, (iv) heterocycle-Q-₄ alkyl (preferably, 5- to 8-membered heterocycle-C^ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like),

(v) optionally halogenated CM alkyloxy,

(vi) C_1-4 alkyl-carbonyl, (vii) cyano,

(viii) carbamoyl optionally substituted by C_1-8 alkyl, and

(ix) Q-₄ alkoxy-carbonyl;

R^lais

(i) a hydrogen atom, (ii) a cyano group, or

(iii) a Cμ alkyl group or a C₂₄ alkenyl group, each of which is optionally substituted by -NR⁸-CO-

(CH₂VNR⁶R⁷ wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ atkyl group, R is a hydrogen atom or a C₁₄ alkyl group, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-; and

R is a Q-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from (a) hydroxy,

(b) carboxy,

(c) cyano,

(d) optionally halogenated CM alkyloxy,

(e) -0-(CH₂VOH, (f) -0-(CH₂VO-CO-NH₂,

(g) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl),

(h) -O-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl),

(i) -0-(CH₂VSO₂-C_6-18 aryl,

O) -O-(CH₂VSO₂-(CH₂VOH, (k) -O-(CH₂)_n-NR⁸-CO-C₁₄ alkyl,

(1) -O-(CH₂)_n-NR⁸-CO-(CH₂VSO₂-C₁₄ alkyl,

(m) -O-(CH₂)_n-NR⁸-SO₂-(optionally halogenated C₁₄ alkyl),

(n) -CO-NR⁸-(CH₂)_n-OH,

(o) -CO-NR⁸-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl), (p) -C0-NR⁸-0-C₁₄ alkyl,

(r) -NR⁸-(CH₂)_n-OH,

(u) -NR⁸-CO-(CH₂)_n-OH,

(v) -NR⁸-CO-(CH₂)_n-CN,

(w) -NR^CO-(CH₂VNR⁶R⁷, 5 (x) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(y) -]NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl),

(z) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(aa) -NR⁸~CO-(CH₂)n-SO₂-C_3-8 cycloalkyl,

(bb) -NR⁸-CO-(CH₂)_n-NR⁸-SO₂-Ci₄ alkyl, o (cc) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(ee) -NR⁸-CO-NH-O-C₁₄ alkyl,

(S) -NR⁸-CO-NH-(CH₂)n-O-C₁₄ alkyl,

(gg) -NR⁸-C(=NH)-NH-C₁₄ alkyl, (hh) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(ii) -S-(CH₂)_n-OH,

(ii) -SO-(CH₂)_n-OH,

(kk) -SO₂-(CH₂VOH, and

(11) -NR⁸-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C_1-4 alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R⁸ is a hydrogen atom or a C₁₄ alkyl group, (CH₂)_n are optionally substituted by halogenated C₁₄ alkyl or hydroxy, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)n is 5 optionally replaced by -CH=CH-;

R^3a is a hydrogen atom or a C_1-6 alkyl group; or R^la and R²¹¹ are optionally bonded to form

R²¹¹ and R^3a are optionally bonded to form C₂₄ alkylene optionally substituted by an imino group, i o particularly preferably, R²⁸ is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group (particularly, a C_1-8 alkyl group), each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) carboxy, is (c) cyano,

(d) optionally halogenated C₁₄ alkyloxy,

(e) -O-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by hydroxy),

(f) -O-(CH₂)_n-O-CO-NH₂,

(g) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl), 0 (h) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(i) -0-(CH₂VSO₂-C_6-I8 aryl, G) -O-(CH₂VSO₂-(CH₂VOH, Qc) -O-(CH₂)_n-NR⁸-CO-C₁₄ alkyl, (1) -O-(CH₂)_n-NR⁸-CO-(CH₂VSO2-Ci4 alkyl, (m) -O-(CH₂VNR⁸-SO₂-(optionally halogenated C₁₄ alkyl), 5 (n) -CO-NR⁸-(CH₂VOH,

(o) -CO-NR⁸-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl),

(p) -CO-NR⁸-O-C₁₄ alkyl,

(Cj) -NR⁶R⁷,

(r) -NR⁸-(CH₂)_n-OH, o (s) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl,

(t) -NR⁸-CO-(optionally halogenated C₁₄ alkyl),

(u) -NR⁸-CO-(CH₂VOH (wherein (CH₂)n is optionally substituted by optionally halogenated C₁₄ alkyl or hydroxy), (v) -NR⁸-CO-(CH₂VCN, 5 (w) -NR⁸-CO-(CH₂)_n-NR⁶R⁷ (when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-), (x) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl, (y) -NR⁸-CO-(CH₂VSO-(optionally halogenated C₁₄ alkyl), (z) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally o substituted by C₁₄ alkyl),

(cc) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl, (dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl, (ee) -NR⁸-CO-NH-O-C₁₄ alkyl, (ff) -NR⁸-CO-NH-(CH₂)_n-O-C₁₄ alkyl, (gg) -NR⁸-C(=NH)-NH-C₁₄ alkyl, (hh) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl, (U) -S-(CH₂VOH, Qj) -SO-(CH₂VOH, (kk) -SO₂-(CH₂VOH, and

(11) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl,

-CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R is a hydrogen atom or a C₁₄ alkyl group, [24] a compound of the compound (Ia) [20], wherein

B^a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated C₁₄ alkyl; C^a is a phenyl group substituted by 1 to 5 substituents selected from

(i) halogen,

(ii) optionally halogenated C₁₄ alkyl,

(iii) hydroxy-C₁₄ alkyl, (iv) heterocycle-C₁₄ alkyl (preferably, 5- to 8-membered heterocycle-C^ alkyl, said 5- to 8- membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like),

(v) optionally halogenated C₁₄ alkyloxy, (vi) cyano, and

(vϋ) carbamoyl optionally substituted by C_1-8 alkyl;

R ^a is a hydrogen atom;

R^ is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group, each of which is substituted by substituent(s) selected from (a) hydroxy,

(b) optionally halogenated C₁₄ alkyloxy,

(c) -O-(CH₂)_n-OH,

(d) -0-(CH₂VO-CO-NH₂,

(e) -O-(CH₂)_n-O-C₁₄ alkyl, (f) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(g) -0-(CH₂VSO₂-C₆-_I8 aryl,

(h) -0-(CH₂VSO₂-(CH₂VOH,

(i) -O-(CH₂)_n-lMR⁸-SO₂-(optionally halogenated C₁₄ alkyl),

O) -CO-NR⁸-(CH₂)_n-OH, (k) -CO-NR⁸-(CH₂)_n-SO₂-(optiona]ly halogenated C₁₄ alkyl),

(1) -NR⁶R⁷,

(m) -NR⁸-(CH₂)_n-OH,

(n) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl, (o) -NR⁸-CO-(CH₂)_n-OH,

(p) ~NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(q) -NR⁸-CO-(CH₂VSO-(optionalry halogenated C₁₄ alkyl),

(r) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), (s) -NR⁸-CO-(CH₂)_n-SO₂-C₃.₈ cycloalkyl,

(t) -NR^CO₂-(CH₂VSO₂-C₁₄ alkyl,

(u) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(v) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(w) -S-(CH₂)_n-0H, (x) -SO-(CH₂)_n-OH,

(y) -SO₂-(CH₂VOH, and

(z) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R and R⁷ are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R⁸ is a hydrogen atom or a C₁₄ alkyl group, and (CH₂)_U is optionally substituted by C₁₄ alkyl or hydroxy; R^3a is a hydrogen atom or a Cw alkyl group; or

R^la and R^2a are optionally bonded to form

R^ and R^3a are optionally bonded to form C₂₄ alkylene, particularly preferably, R²*¹ is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group (particularly, a C_1-8 alkyl group), each, of which is substituted by substituent(s) selected from 5 (a) hydroxy,

(b) optionally halogenated C₁₄ alkyloxy,

(c) -O-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by hydroxy),

(d) -0-(CH₂VO-CO-NH₂, (e) -O-(CH₂)_n-O-C₁₄ alkyl, o (f) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(g) -0-(CH₂VSO₂-C_6-18 aryl,

(h) -0-(CH₂VSO₂-(CH₂VOH₅

(i) -O-(CH₂)_n-NR⁸-SO₂-(optionally halogenated C₁₄ alkyl),

(j) -CO-NR⁸-(CH₂)_n-OH, (k) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(1) -NR⁶R⁷, (m) -NR⁸-(CH₂)_n-OH, (n) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl,

(o) -NR⁸-CO-(CH₂)_n-OH (wherein CH₂)_n is optionally substituted by C₁₄ alkyl), (p) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(q) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl),

(r) -NR⁸-CO-(CH₂)_n-SO₂-(oρtionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C_1-4 alkyl),

(s) -NR⁸-CO-(CH₂VSθ2-C₃-8 cycloalkyl,

(t) -NR⁸-CO₂-(CH₂)n-SO₂-C₁₄ alkyl,

(u) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl, (v) -NR⁸-SO₂-(CH₂VSO₂-C₁₄ alkyl,

(w) -S-(CH₂)_n-OH,

(X) -SO-(CH₂VOH,

(y) -SO₂-(CH₂VOH, and

(z) -NR⁸-CO-(optionaUy substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, and R is a hydrogen atom or a C₁₄ alkyl group, [25] the compound of the above-mentioned [23], wherein

R^2a is (i) a C_5-8 alkyl group substituted by hydroxy,

(ϋ) a C_1-8 alkyl group substituted by substituent(s) selected from

(a) halogenated C₁₄ alkyloxy, O) -O-(CH₂VOH,

(c) -0-(CH₂VO-CO-NH₂,

(d) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl),

(e) -O-(CH₂VSO₂-(optionalry halogenated C₁₄ alkyl), Ct) -0-(CH₂VSO₂-C_6-18 aryl,

(g) -O-(CH₂)_tχ-NR⁸-SO₂-(oρtionally halogenated C₁₄ alkyl), . Ch) -CO-NR⁸-(CH₂VOH,

(i) -CO-NR⁸-(CH₂)_n-SO₂-(oρtionally halogenated C_1-4 alkyl), 5 O) -NR⁸-(CH₂)_n-SO₂-Ci4 alkyl, (k) -NR⁸-CO-(CH₂)_n-OH, (1) -M^-CO-(CH₂VO-C₁₄ alkyl,

(m) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl), (n) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), o (o) -NR⁸-CO-(CH₂)_n-SO₂-C_3-8 cycloalkyl,

CP) -NR⁸-CO₂-(CΉ₂>SO₂-C₁₄ ^_I5

(q) -NR⁸-CO-NH-(CH₂VSO₂-C₁₄ alkyl, (r) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl, (S) -S-(CH₂VOH, s (t) -SO-(CH₂VOH, (u) -SO₂-(CH₂VOH, and

(v) -NR⁸-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by o substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, -

CO-NH-Ci₄ alkyl, -CONH₂, -SO₂-Ci₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R is a hydrogen atom or a Ci₄ alkyl group, and (CH₂)_n is optionally substituted by Ci₄ alkyl or hydroxy, (iϋ) a C_2-8 alkenyl group optionally substituted by hydroxy, or (iv) a C_2-8 alkynyl group optionally substituted by hydroxy, particularly preferably, R^2a is (i) a C_5-8 alkyl group substituted by hydroxy, (ϋ) a C_1-8 alkyl group substituted by substituent(s) selected from 5 (a) halogenated CM alkyloxy,

(b) -O-(CH₂)n-OH (wherein (CH₂)_n is optionally substituted by hydroxy), (c) -0-(CH₂VO-CO-NH₂,

(d) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl),

(e) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), i o (f) -O-(CR₂)_n-SO₂-Cw aryl,

(g) -O-(CH₂)_n-NR⁸-SO₂-(optionally halogenated C₁₄ alkyl),

(h) -CO-Mt⁸-(CH₂)_n-OH,

(i) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

O) -NR⁸-(CH₂)_n-SO₂-Ci₄ alkyl, 5 (k) -NR⁸-CO-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(1) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(m) -NR⁸-CO-(CH₂)_n-SO-(oρtionally halogenated C₁₄ alkyl),

(n) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl), 0 (o) -NR⁸-CO-(CH₂)_n-SO₂-C_3-8 cycloalkyl,

(p) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(q) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(r) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl, (s) -S-(CH₂)_n-OH,

(t) -SO-(CH₂VOH,

(u) -SO₂-(CH₂VOH, and

(v) -NR ~CO-(optionaUy substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, CM atkyl, optionally oxidized C₁₄ alkylthio, -CO-C_1-4 alkyl, -

CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a C₁₄ alkyl group, (iϋ) a C_2-8 alkenyl group optionally substituted by hydroxy, or

(iv) a C_2-8 alkynyl group optionally substituted by hydroxy, [26] a compound of the compound (Ta) [20], wherein

R ^a is (i) a hydrogen atom or

(ii) a group represented by the formula -X -R , wherein X² is a single bond, -NH- or -0-, and

R⁴ is (i) a hydrogen atom,

(ϋ) a cyano group,

(iϋ) a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a C_1-8 alkyl-carbonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-C₁₄ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C₁₄ alkyl-carbonyl group, a heterocyclic group (e.g., a 5- to 8-membered heteroaryl group containing, as an atom (ring atom) constituting a ring system, 1 to 4 hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom (preferably, an oxygen atom, a sulfur atom and a nitrogen atom) or a saturated or unsaturated aliphatic heterocyclic group), a heterocycle-Q.₄ alkyl group, aheterocycle-carbonyl group or aheterocycle-C^ alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group T, or

(iv) a carbamoyl group optionally having 1 or 2 C_1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituent(s) selected from substituent group T, R²*¹ is (i) a hydrogen atom, (ii) a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Q-₄ alkyl group, a C_6-1S aryl-carbonyl group, a C_6-18 aryl-C^ alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C^ alkyl group, aheterocycle-carbonyl group or aheterocycle- C_1-4 alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from substituent group T, or

(iϋ) a carbamoyl group optionally having 1 or 2 C_1-8 alkyl group(s) optionally substituted by substituent(s) selected from substituent group T, wherein the carbamoyl group has two substituents, and they optionally form, together with the adjacent nitrogen atom, a 3- to 8-membered saturated or an unsaturated aliphatic heterocyclic group, which is optionally substituted by substituent(s) selected from substituent group T, or

R^la and R^, or R^2a and R^3a are optionally bonded to form a saturated or unsaturated 4- to 8- membered heterocycle optionally substituted by 1 to 5 substituents selected from substituent group

T, R ^a is (i) a hydrogen atom, or

(ii) a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group or a C_3-8 cycloalkyl group, each of which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, CM alkyloxy, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM 5 alkyl-carbonylamino, CM alkoxy-carbonylamino and CM alkylsulfonylamino, or

R^3a is optionally bonded to a carbon atom of the adjacent phenyl group to form a saturated or unsaturated 4- to 8-membered nitrogen-containing heterocycle, which is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, CM alkyloxy, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy- i o carbonylamino and CM alkylsulfonylamino,

B^a is a benzene ring optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, CM alkyloxymethyl, hydroxy-C_M alkyl, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM

15 alkylsulfonylamino, and

C^a is a C_6-18 aryl group optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated CM alkyloxy, CM alkyloxymethyl, hydroxy-C_M alkyl, CM alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, CM alkyl-carbonylamino, CM alkoxy-carbonylamino and CM 0 alkylsulfonylamino.

The compound (Ia) that is an AMPK activator and to be at least one of compounds administered to a mammal to protect heart in this method may be a compound (Ia') represented by the following formula [27], a salt thereof, or a prodrug thereof [28] (sometimes collectively to be referred to as compound (Ta') in the present specification):

wherein

5 p R la is a hydrogen atom,

R ,2a is a Cw alkyl group substituted by a group represented by -NR 6a -CO-(CH₂)_n-Sθ₂-optionally halogenated C^ alkyl wherein n is an integer of 1 to 4, R^6a is a hydrogen atom or a C^ alkyl group, and -(CH₂)_n- is optionally substituted by C^ alkyl, ° R^3a is a hydrogen atom or a Cw alkyl group,

R^4a is a halogen atom or a Cw alkyl group,

R^5a is a halogen atom or a C_1-6 alkyl group, and

X^a is a hydrogen atom or a halogen atom, or a salt thereof, provided that N- [2-(4- { [3 -chloro-4-(3 -chlorophenoxy)phenyl] amino} -5H-pyrrolo[3 ,2-d]pyrimidin-

5-yl)ethyl]-2-(methylsulfonyl)acetamide is excluded.

In the present specification, unless otherwise specified, the "aryl" in the "aryl group" and the substituents includes a monocyclic aryl group and a fused polycyclic aryl group. As the "aryl group", for example, a C_6-18 aryl group can be mentioned. As the "C_6-18 aryl group", for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryl and acenaphthylenyl can be mentioned.

In the present specification, as the "heterocyclic group" (and "heterocycle-" in the substituents), for example, a 5- to 8-membered heteroaryl group or a saturated or unsaturated 5 aliphatic heterocyclic group containing, as an atom (ring atom) constituting a ring system, one or more (preferably 1 to 4, more preferably 1 or 2) hetero atoms selected from an oxygen atom, an optionally oxidized sulfur atom and a nitrogen atom and the like (preferably, an oxygen atom, a sulfur atom and a nitrogen atom etc.) can be mentioned.

In the present specification, unless otherwise specified, as the "aliphatic hydrocarbon i o group", a linear or branched aliphatic hydrocarbon group having 1 to 15 carbon atom (preferably, 1 to 8 carbon atom) can be mentioned. As such "aliphatic hydrocarbon group", for example, a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a C_3-8 cycloalkyl group and the like can be mentioned.

In the present specification, unless otherwise specified, as the "heteroaryl group", an 15 aromatic monocyclic heterocyclic group (e.g., 5- or 6-membered aromatic monocyclic heterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, l,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like) and an aromatic fused heterocyclic group (e.g., 8 to 0 12-membered aromatic fused heterocyclic group such as benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, lH-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acrydinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenathridinyl, phenathrolinyl, indolizinyl, pyrrolo[l,2-b]pyridazinyl, pyrazolo[l,5-a]pyridyl, imidazo[l,2-a]pyridyl, imidazo[l,5-a]pyridyl, imidazo[l,2-b]pyridazinyl, inτidazo[l,2-a]pyrinτidinyl, l,2,4-triazolo[4,3-a]pyridyl, l,2,4-triazolo[4,3-b]pyridazinyl and the 5 like) and the like can be mentioned. As the aromatic fused heterocyclic group, a heterocycle wherein the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group is fused with a benzene ring and a heterocycle wherein the same or different two heterocycles of the aforementioned 5- or 6-membered aromatic monocyclic heterocyclic group are fused are preferable. In the present specification, unless otherwise specified, as the "aliphatic heterocyclic group", i o for example, a 3- to 8-membered (preferably 5- or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomoφholinyl, piperazinyl, dihydro-l,2,4-oxadiazolyl and the like, and the like can be mentioned.

In the present specification, unless otherwise specified, as the "C_1-8 alkyl group", for is example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t- pentyl, neopentyl, n-hexyl, i-hexyl, n-heptyl and n-octyl and the like can be mentioned, with preference given to a C₁^ alkyl group. In the present specification, moreover, unless otherwise specified, as the "C₁^ alkyl group", for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and i- butyl can be mentioned. 0 In the present specification, unless otherwise specified, as the "C_2-8 alkenyl group", for example, vinyl, (1- or 2-)propenyl, (1-, 2- or 3-)butenyl, pentenyl, octenyl and (l,3-)butadienyl can be mentioned, with preference given to a C₂^ alkenyl group.

In the present specification, unless otherwise specified, as the "C_2-8 alkynyl group", for example, ethynyl, (1- or 2-)propynyl, (1-, 2- or 3-)butynyl, pentynyl and octynyl can be mentioned, with preference given to a C₂₄ alkynyl group.

In the present specification, unless otherwise specified, as the "C₃.₈ cycloalkyl group", for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl can be 5 mentioned, with preference given to a C₃^ cycloalkyl group.

In the present specification, unless otherwise specified, as the "CM alkylene", for example, methylene, ethylene, trimethylene, tetramethylene and propylene and the hike can be mentioned.

In the present specification, unless otherwise specified, as the "-0-(CM alkylene)-", for example, -OCH₂-, -OCH₂CH₂-, -O(CH₂)₃-, -O(CH₂)₄-, -OCH(CH₃)-, -OC(CH₃)₂-, i o -OCH(CH₃)CH₂-, -OCH₂CH(CH₃)-, -OC(CH₃)₂CH₂- and -OCH₂C(CH₃)₂- and the like can be mentioned.

In the present specification, unless otherwise specified, as the "C_6-18 aryl-carbonyl group", for example, benzoyl, naphthoyl, anthrylcarbonyl, phenanthrylcarbonyl and acenaphthylenylcarbonyl and the like can be mentioned.

15 In the present specification, unless otherwise specified, as the "C_6-18 aryl-C^ alkyl-carbonyl group", for example, benzylcarbonyl, 3-phenylpropionyl, 2-phenylpropionyl, 4-phenylbutyryl and 5-phenylpentanoyl and the like can be mentioned.

In the present specification, unless otherwise specified, as the "halogen", fluorine, chlorine, bromine and iodine can be mentioned. 0 As the "5- to 8-membered heterocycle-carbonyl group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom", "a 5- to 8-membered cyclic amino-carbonyl group optionally having 1 or 2 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom" is preferable, for example, pyrrolidin-1-ylcarbonyl, piperidin-1- ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4-ylcarbonyl and the like can be mentioned.

In the above-mentioned formula, as the "aryl group" for A, a C_6-18 aryl group is preferable, and phenyl is more preferable. The "aryl group" is optionally substituted by a group of the formula -Y -B, wherein Y is a single bond, -O-, -0-(C_1-3 alkylene)- (preferably -OCH₂-), -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-Ci₄ alkyl-carbonyl group, each of which is optionally substituted.

As Y , a single bond, -O- or -OCH₂- is preferable, and -O- or -OCH₂- is more preferable. As the "aryl group" for B, a C_6-18 aryl group is preferable, and phenyl is more preferable.

As the "heterocyclic group" for B, the aforementioned "5 or 6-membered aromatic monocyclic heterocyclic group" is preferable, and pyridyl is more preferable.

The "aryl group", "heterocyclic group", "C_6-18 aryl-carbonyl group" or "C_6-18 aryl-C^ alkyl-carbonyl group" for B may have, for example, 1 to 5, the same or different substituents selected from halogen, optionally halogenated Cμ alkyl, hydroxy, optionally halogenated C_M alkyloxy, C₁^ alkyloxymethyl, hydroxy-Cw alkyl, C_1-4 alkyl-carbonyl, carboxy, C₁^ alkoxy- carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₄ alkyl-carbonylamino, CM alkoxy- carbonylamino and C₁^ alkylsulfonylamino, at any substitutable position(s).

The "aryl group" for A may have, besides a group of the above-mentioned formula -Y -B, 1 to 5, the same or different substituents at any substitutable position(s). As such substituent, substituents similar to those exemplified for "aryl group" or "heterocyclic group" for B can be mentioned.

As the "aliphatic hydrocarbon group" for R , a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group and a C_3-8 cycloalkyl group are preferable.

The "aliphatic hydrocarbon group" for R is optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C₁₄ alkyloxy, C₁₄ alkyl-carbonyl, carboxy, CM alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₄ alkyl-carbonylamino, C₁₄ alkoxy-carbonylamino and Cj₄ alkylsulfonylamino.

The "C_1-4 alkylene" and "-0-(C₁₄ alkylene)-" for Y¹ are optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, C₁₄ alkyloxy, C₁₄ alkyl-carbonyl, carboxy, C₁₄ alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C₁₄ alkyl-carbonylamino, C₁₄ alkoxy- carbonylamino and C₁₄ alkylsulfonylamino. As X¹, -NR³- wherein R³ is as defined above is preferable.

As the "optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom" for R , a group of the formula -X -R can be mentioned, wherein X is a single bond, -NH- or -O-, and R is a hydrogen atom, a cyano group, or a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-C₁₄ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C₁₄ alkyl-carbonyl group, a heterocyclic group, aheterocycle-C₁₄ alkyl group, aheterocycle-carbonyl group or a heterocycle-C₁₄ alkyl-carbonyl group, each of which is optionally substituted.

The "C_1-8 alkyl group", "C_2-8 alkenyl group", "C_2-8 alkynyl group", "C_1-8 alkyl-carbonyl group", "C_3-8 cycloalkyl group", "C_6-18 aryl group", "C_6-18 aryl-C₁₄ alkyl group", "C_6-18 aryl- carbonyl group", "C_6-18 aryl-C₁₄ alkyl-carbonyl group", "heterocyclic group", "heterocycle-C_M alkyl group", "heterocycle-carbonyl group" and "heterocycle-C^ alkyl-carbonyl group" are, for example, optionally substituted by one or more (preferably 1 to 5, more preferably 1 to 3) substituent(s) selected from (a) halogen,

(b) oxo,

(c) optionally halogenated CM alkyl,

(d) -(CH₂)_m-Q, (e) -(C^_m-Z^Coptionally halogenated C₁₄ alkyl),

(g) -(CH₂)πrZ²-(CH₂)_n-Q,

(h) -(CH₂)_m-Z²-(CH₂)_n-Z¹-(optionally halogenated C₁₄ alkyl),

(i) -(CH₂)_m-Z²-(CH₂)_n-Z¹-C_3-B cycloalkyl, (j) -(CH^_m-Z^optionalry substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom)

(k) -(CH₂)_m-Z²-C₁₄ alkoxy, and

(1) -(CH^_m-Z^^H^_n-Z^^H^_n-Z^C_M alkyl (hereinafter to be sometimes to be referred to as substituent group T).

In these formulas, m is an integer of 0 to 4, n is an integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro, -NR⁶R⁷, -CONR⁶R⁷ or -SO₂NR⁶R⁷, Z¹ is -O-, -CO-, -C(OH)R⁸-, -C(=N-0R⁸)-,

-S-, -SO-, -SO₂-, -N(COR⁸)-, -N(CO₂R⁹)-, -N(SO₂R⁹)-, -CO-O-,

-0-C0-, -CO-NR⁸-, -NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH-, -NR⁸-SO₂-, or -NR⁸-C(=NH)-NH-, and Z² is -0-, -CO-, -C(OH)R⁸-, -C(=N-0R⁸)-,

-S-, -SO-, -SO₂-, -NR⁸-, -N(COR⁸)-, -N(CO₂R⁹)-, -N(SO₂R⁹)-,

-CO-O-, -0-C0-, -CO-NR⁸-, -NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH-,

-NR⁸-C(=NH)-NH-, -NR⁸-SO₂-, or -SO₂-NR⁸-. In these formulas, (CH₂)_m and (CH₂)_n are optionally substituted by one or more (preferably 1 to 5, more preferably 1 to 3) substituents selected from, for example, halogen, optionally halogenated Cu alkyl and hydroxy, and when m or n is not less than 2, a subset -CH₂CH₂- of (CH₂)_m and (CH₂)_n is optionally replaced by -CH=CH- or -OC-. In these formulas, R and R are the same or different and each is a hydrogen atom or CM alkyl, or R⁶ and R⁷ form a ring together with a nitrogen atom. In these formulas, moreover, R⁸ is a hydrogen atom or Q₄ alkyl and R⁹ is C₁4 alkyl. When R⁶ and R⁷ form a ring together with a nitrogen atom, as the nitrogen-containing heterocyclic group, for example, a 3 to 8-membered (preferably 5 or 6-membered) saturated or unsaturated (preferably saturated) aliphatic heterocyclic group such as azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, heptamethyleneimino, morpholinyl, thiomorphoUnyl, piperazinyl, homopiperazinyl and the like, and the like can be mentioned.

As X², a single bond is preferable.

As R , a hydrogen atom or a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_6-18 aryl group or heterocyclic group, each of which is optionally substituted is preferable. As the "C₆₄₈ aryl group" for R⁴, phenyl is preferable. As the "heterocyclic group" for R⁴, the aforementioned "5 or 6- membered aromatic monocyclic heterocyclic group" is preferable, and furyl is preferable.

As the "optionally substituted group bonded via a carbon atom or a sulfur atom" for R², a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Cu alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C^ alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, a heterocycle-C^ alkyl group, a heterocycle-carbonyl group or a heterocycle-

Ci-4 alkyl-carbonyl group, each of which is optionally substituted, can be mentioned. The "Q-₈ alkyl group", "C_2-8 alkenyl group", "C_2-8 alkynyl group", "C_1-8 alkyl-carbonyl group", "C_1-8 alkylsulfonyl group", "C_3-8 cycloalkyl group", "C_6-18 aryl group", "C_6-18 aryl-C^ alkyl group", "C_6-18 aryl-carbonyl group", "C_6-18 aryl-C^ alkyl-carbonyl group", "C_6-18 aryl-sulfonyl group", "heterocyclic group", "heterocycle-C^ alkyl group", "heterocycle-carbonyl group" and 5 "heterocycle-C^ alkyl-carbonyl group" are optionally substituted by, for example, one or more (preferably 1 to 5, more preferably 1 to 3) substituents selected from the above-mentioned substituent group T.

As R², a hydrogen atom or a C_1-8 alkyl group, a C_6-18 aryl group, a C_6-18 aryl-C^ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-sulfonyl group or heterocycle-Cw alkyl group, each of i o which is optionally substituted, is preferable.

As the "C_6-18 aryl group" for R², phenyl is preferable. As the "C_6-18 aryl-Cw alkyl group" for R , benzyl is preferable. As the "C_6-18 aryl-carbonyl group" for R , benzoyl is preferable. As the "C_6-18 aryl-sulfonyl group" for R², phenylsulfonyl is preferable. As the "heterocyclic group" or "heterocycle-" of "heterocycle-C^ alkyl group", "heterocycle-carbonyl group" and "heterocycle- 15 Q₄ alkyl-carbonyl group" for R², the aforementioned "5 or 6-membered aromatic monocyclic heterocyclic group" or the aforementioned "aliphatic heterocyclic group" is preferable, and furyl or tetrahydrofuryl is preferable.

In the substituents that a group represented by R may have, when R and R form a ring together with a nitrogen atom, the "ring" optionally further has 1 to 5 (preferably 1 to 3) the same or 0 different substituents. As such substituents, substituents similar to those exemplified for "aryl group" or "heterocyclic group" for B can be mentioned.

The aforementioned "carbamoyl group" and "ureido group" optionally have 1 or 2 optionally substituted C_1-8 alkyl group(s). Alternatively, the "carbamoyl group" and "ureido group" may have two substituents and they may form an optionally substituted ring, together with the adjacent nitrogen atom. As the "ring" of the "optionally substituted ring", rings similar to those formed by R⁶ and R⁷ together with a nitrogen atom as exemplified above can be mentioned. As the "substituent" of the "optionally substituted C_1-8 alkyl group" and as the "substituent" of the "optionally substituted ring", groups similar to the substiruents of the above-mentioned substituent group T can be mentioned.

As the "optionally substituted carbamoyl group", carbamoyl, C_1-8 alkylcarbamoyl, di(C_1-8 alkyl)carbamoyl, C_6-18 aryl-C^ alkylcarbamoyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, piperazin-1-ylcarbonyl, morpholin-4-ylcarbonyl, thiomorpholin-4- ylcarbonyl, (C^ alkyl)piperidin-l-ylcarbonyl, (C_6-18 aryl-Cw alkyl)piperidin-l-ylcarbonyl and the like can be mentioned.

As the "optionally substituted ureido group", ureido, 3-(C_1-8 alkyl)ureido, 3,3-di(C_1-8 alkyl)ureido, 3-(C_6-18 aryl-C^ alkyl)ureido, azetidine-1-ylcarbonylarnino, pyrrolidin-1- ylcarbonylamino, piperidin-1-ylcarbonylamino, piperazin-1-ylcarbonylamino, rnorpholin-4- ylcarbonylamino, thiomoφholin-4-ylcarbonylamino, (CM alkyl)piperidin- 1 -ylcarbonylamino, (C₆. _I8 aryl-Q-₄ alkyl)piperidin-l -ylcarbonylamino and the like can be mentioned.

As the "ring structure" of the optionally substituted ring structure formed by R³ bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) nitrogen- containing heterocycle can be mentioned. Specifically,

The "ring structure" may have 1 to 5 (preferably 1 to 3, more preferably 1 or 2) the same or different substituents at any substitutable position(s). As such substituents, substituents similar to those exemplified for "aryl group" or "heterocyclic group" for B can be mentioned.

As the "ring structure" of the optionally substituted ring structure formed by R¹ and R² bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- or 6-membered) heterocycle can be mentioned. When R and R² are bonded to form an optionally substituted ring structure, for example,

i o wherein each symbol is as defined above, and the like can be mentioned.

As the "ring structure" of the optionally substituted ring structure formed by R² and R³ bonded to each other, a saturated or unsaturated (preferably saturated) 4- to 8-membered (preferably 5- to 7-membered) heterocycle can be mentioned. When R² and R³ are bonded to form an optionally substituted ring structure, for example,

wherein each symbol is as defined above, and the like can be mentioned. The "ring structure"

formed by R¹ and R², or R² and R³ bonded to each other may have 1 to 5 (preferably 1 to 3, more

preferably 1 or 2) the same or different substituents selected from the above-mentioned substituent

group T at any substitutable position(s).

When W is C(R¹), compound (T) is represented by the following formula (IA):

(IA) wherein each symbol is as defined above.

When W is N, compound (T) is represented by the following formula (TB) or (IC):

(IB) (IC)

wherein each symbol is as defined above.

Specifically, as the compound (I), the following compound (Ia) and the like are preferably

used. A compound represented by the formula:

wherein R^la is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R²*¹ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R ^a and R , or R²⁸ and R^3a are optionally bonded to form an optionally substituted ring structure, R^3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R^3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B^a is an optionally substituted benzene ring, and C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

As the "optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom" for R^la, those similar to the "optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom" for R can be used. As the "optionally substituted group bonded via a carbon atom or a sulfur atom" for R , those similar to the "optionally substituted group bonded via a carbon atom or a sulfur atom" for R can be used.

As the "optionally substituted ring structure" formed by R^la and R²⁸, or R^2a and R^3a bonded

1 0 0 to each other, those similar to the "optionally substituted ring structure" formed by R and R , or R and R³ bonded to each other can be used.

As the "optionally substituted aliphatic hydrocarbon group" for R^3a, those similar to the "optionally substituted aliphatic hydrocarbon group" for R³ can be used.

As the "optionally substituted ring structure" for R^3a, which is formed by binding to a carbon atom of the adjacent phenyl group, those similar to the "optionally substituted ring structure" for R³, which is formed by binding to a carbon atom of the adjacent phenyl group can be used.

As the substituent of the "optionally substituted benzene ring" for B^a, for example, 1 to 5, the same or different substituents selected from halogen, optionally halogenated CM alkyl, hydroxy, optionally halogenated Q₄ alkyloxy, Q₄ alkyloxymethyl, hydroxy-C^ alkyl, C₁^ alkyl-carbonyl, carboxy, C₁^ alkoxy-carbonyl, cyano, carbamoyl, sulfamoyl, nitro, amino, C_1-4 alkyl- carbonylamino, C₁^ alkoxy-carbonylamino and C_1-4 alkylsulfonylamino can be used.

As the "C_6-18 aryl group" of the "optionally substituted C_6-18 aryl group" for C^a, for example, phenyl, biphenylyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like can be used, with preference given to a phenyl group. As the "substituent" of the "optionally substituted C_6-18 aryl group" for C^a, those similar to the substituents of the "optionally substituted benzene ring" for B^a can be used.

As R²³, a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-Ci₄ alkyl group, a C_6-I8 aryl-carbonyl group, a C_6-18 aryl-Cπ alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, a heterocycle-Q-₄ alkyl group, a heterocycle-carbonyl group or a heterocycle-C^ alkyl-carbonyl group, each of which is optionally substituted by 1 to 5 substituents selected from

(a) halogen, (b) oxo,

(c) optionally halogenated CH alkyl, (d) -(CH₂)_m-Q,

(e) -(CH₂)_Hi-Z -(optionally halogenated Cμ alkyl), (f) -(CH₂VZ¹"^ cycloalkyl,

(h) -(CH₂)_m-Z²-(CH₂)_n-Z¹-(optionally halogenated C₁₄ alkyl),

(i) -(CH^-Z^CH^-Z¹^ cycloalkyl,

(j) -(CH₂)_m-Z -(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom),

(k) -(CH₂)m-Z²-C_M alkoxy, and

(1) -(CE₂)_m'Z²-(CH₂)_a-Z¹-(C}i₂)_n-Z^l-C_M alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4, Q is hydroxy, carboxy, cyano, nitro, -NR⁶R⁷, -CONR⁶R⁷, -OCONH₂ or -SO₂NR⁶R⁷,

Z¹ is -O-, -CO-, -C(OH)R⁸-, -C(=N-OR⁸>, -S-, -SO-, -SO₂-,

-N(COR⁸)-, -N(CO₂R⁹)-, -N(SO₂R⁹)-, -CO-O-, -0-C0-, -CO-NR⁸-,

-NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH-, -NR⁸-SO₂-, or -NR⁸-C(=NH)-NH-,

Z² is -0-, -CO-, -C(OH)R⁸-, -C(=N-0R⁸)-, -S-, -SO-, -SO₂-, -NR⁸-, -N(COR⁸)-, -N(CO₂R⁹)-, - N(SO₂R⁹)-, -CO-O-, -0-C0-, -CO-NR⁸-,

-NR⁸-C0-, -NR⁸-CO₂-, -NR⁸-C0-NH-, -NR⁸-C(=NH)-NH-₅ -NR⁸-SO₂-, or -SO₂-NR⁸-,

(CH₂)_m and (CH₂)_n are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated C₁₄ alkyl and hydroxy, and when m or n is not less than 2, a subset - CH₂CH₂- of (CH₂)_m and (CH₂)_n is optionally replaced by -CH=CH- or -OC-,

R and R are the same or different and each is a hydrogen atom or a C_1-4 alkyl group, or R and R are bonded to form, together with a nitrogen atom, a 3- to 8-membered saturated or unsaturated aliphatic heterocyclic group,

5 R is a hydrogen atom or CM alkyl, and R is CM alkyl, is preferable. As compound (Ia), a compound wherein

B^a is a benzene ring optionally substituted by 1 to 4 substituents selected ftom halogen, C_1-4 alkyl, hydroxy-Ci₄ alkyl and CM alkyloxy;

C^a is a phenyl group optionally substituted by 1 to 5 substituents selected from (i) halogen, (ii) i o optionally halogenated CM alkyl, (iii) hydroxy-C^ alkyl, (iv) heterocycle-C^ alkyl (preferably, 5- to 8-membered heterocycle-Ci-₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl, triazolyl and the like), (v) optionally halogenated CM alkyloxy, (vi) CM alkyl-carbonyl,

(vii) cyano, (viii) carbamoyl optionally substituted by C_1-8 alkyl and (ix) CM alkoxy-carbonyl; 15 R^lais

(i) a hydrogen atom,

(ϋ) a cyano group, or

(iii) a CM alkyl group or a Q₂₄ alkenyl group, each of which is optionally substituted by -NR⁸-C0-

(CH₂VNR⁶R⁷ 0 wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a CM alkyl group, R is a hydrogen atom or a CM alkyl group, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-;

R^2a is a Ci-₈ alkyl group, a C₂-g alkenyl group or a C₂.g alkynyl group, each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) carboxy,

(c) cyano, (d) optionally halogenated CM alkyloxy, (e) -0-(CH₂VOH,

(f) -0-(CH₂VO-CO-NH₂,

(g) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl), (h) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), (i) -0-(CH₂VSO₂-C_6-I8 aryl,

O) -O-(CH₂VSO₂-(CH₂VOH,

(k) -O-(CH₂)_n-NR⁸-CO-C₁₄ alkyl,

(1) -O-(CH₂VNR⁸-CO-(CH₂VSO₂-C_1-4 alkyl,

(m) -O-(CH₂)_n-NR⁸-SO₂-(optionally halogenated C₁₄ alkyl), (n) -CO-NR⁸-(CH₂)_n-OH,

(o) -CO-NR⁸-(CH₂VSO₂-(optionally halogenated C₁₄ alkyl),

(p) -CO-NR⁸-O-C₁₄ alkyl,

(Cj) -NR⁶R⁷,

(r) -NR⁸-(CH₂VOH, (s) -NR⁸-(CH₂VSO₂-C₁₄ alkyl,

(t) -NR⁸-CO-(optionally halogenated C₁₄ alkyl),

(u) -NR⁸-CO-(CH₂)_n-OH,

(v) -NR⁸-CO-(CH₂)_n-CN, (w) -NR^CO-(CH₂VNR⁶R⁷,

(x) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(y) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl),

(z) -NR⁸-CO-(CH₂)_n-S0₂-(optionally halogenated C₁₄ alkyl), 5 (aa) -NR⁸-CO-(CH₂)n-SO₂-C3-8 cycloalkyl,

(bb) -NR⁸-CO-(CH₂)_n-NR⁸-SO₂-C₁₄ alkyl,

(cc) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(ee) -NR⁸-CO-NH-O-C₁₄ alkyl, i o (ff) -NR⁸-CO-NH-(CH₂VO-C₁₄ alkyl,

(gg) -NR⁸-C(=NH)-NH-C₁₄ alkyl,

(hh) -NR⁸-SO₂-(CH₂)n-SO₂-C₁₄ alkyl,

(M) -S-(CH₂VOH,

Qi) -SO-(CH₂VOH, is (kk) -SO₂-(CH₂VOH, and

(11) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, - 0 CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl,

-CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R⁶ and R⁷ are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R is a hydrogen atom or a C₁₄ alkyl group, (CH₂)_n is optionally substituted by optionally halogenated CM alkyl or hydroxy, and when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-; and R^3a is a hydrogen atom or a Cw alkyl group; or R^la and R²* are optionally bonded to form

R²*¹ and R^3a are optionally bonded to form C₂₄ alkylene optionally substituted by an irnino group is preferable.

As R⁸, a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable. As R , a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group, each of which is optionally substituted by substituent(s) selected from

(a) hydroxy,

(b) carboxy,

(c) cyano, (d) optionally halogenated CM alkyloxy,

(e) -O-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by hydroxy),

(f) -0-(CH₂VO-CO-NH₂,

(g) -O-(CH₂)_n-O-(optionally halogenated C₁^ alkyl), (h) -O-(CH₂)_n-SO₂-(optionally halogenated C_1-4 alkyl), (i) -O-(CH₂)_n-SO₂-C₆.i₈ aryl, Q) -O-(CH₂)_n-SO₂-(CH₂)_n-OH,

(k) -O-(CH₂)_n-NR⁸-CO-C_M alkyl, (1) -O-(CH₂)_n-NR⁸-CO-(CH₂)_n-SO₂-C₁₄ alkyl,

(m) -O-(CH₂)_n-NR⁸-SO₂-(optionally halogenated C₁₄ alkyl),

(n) -CO-NR⁸-(CH₂)_n-OH,

(o) -CO-NR⁸-(CH₂)_n-SO₂-(oρtionally halogenated C₁₄ alkyl), 5 (p) -CO-NR⁸-O-C₁₄ alkyl,

Cq) -NR⁶R⁷,

(r) -NR⁸-(CH₂)_n-OH,

(s) -NR^(CH₂VSO₂-C₁₄ alkyl,

(t) -NR⁸-CO-(optionally halogenated C₁₄ alkyl), i o (u) -NR⁸-CO-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by optionally halogenated C₁₄ alkyl or hydroxy),

(v) -NR⁸-CO-(CH₂)_n-CN,

(w) -NR⁸-CO-(CH₂)_n-NR⁶R⁷ (when n is not less than 2, a subset -CH₂CH₂- of (CH₂)_n is optionally replaced by -CH=CH-), is (x) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(y) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl),

(z) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(aa) -NR⁸-CO-(CH₂)_n-SO₂-C_3-8 cycloalkyl, 0 (bb) -NR⁸-CO-(CH₂)_n-NR⁸-SO₂-C₁₄ alkyl,

(cc) -NR⁸-CO₂-(CH₂)_n-SO₂-C₁₄ alkyl,

(dd) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(ee) -NR⁸-CO-NH-O-C₁₄ alkyl, (ff) -NR^CO-NH-(CH₂VO-C₁₄ alkyl,

(gg) -NR⁸-C(=NH)-NH-C₁₄ alkyl,

(bh) -NR^SO₂-(CH₂VSO₂-C₁₄ alkyl,

(U) -S-(CH₂VOH, 5 (U) -SO-(CH₂VOH,

(kk) -SO₂-(CH₂VOH, and

CO-O-C₁₄ alkyl, -CO-NH-C₁₄ alkyl,

-CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, and R⁸ is a hydrogen atom or a C₁₄ alkyl group, is preferable. is As R⁸, a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.

As compound (Ia), moreover, a compound wherein

B^a is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated C₁₄ alkyl; 0 C^a is a phenyl group substituted by 1 to 5 substituents selected from (i) halogen, (ii) optionally halogenated C₁₄ alkyl, (Mi) hydroxy-C₁₄ alkyl, (iv) heterocycle-C₁₄ alkyl (preferably, 5- to 8- membered heterocycle-C₁₄ alkyl, said 5- to 8-membered heterocycle has 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, such as imidazolyl and the like), (v) optionally halogenated C₁₄ alkyloxy, (vi) cyano, and (vii) carbamoyl optionally substituted by C_1-8 alkyl; R^la is a hydrogen atom;

R^ is a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group, each of which is substituted by substituent(s) selected from

(a) hydroxy,

(b) optionally halogenated CM alkyloxy, (c) -O-(CH₂)_n-OH,

(d) -0-(CH₂VO-CO-NH₂, (e) -0-(CH₂)_n-0-C₁₄ alkyl,

(f) -O-(CH₂)_n-SO₂-(optionally halogenated C_1-4 alkyl),

(g) -0-(CH₂VSO₂-C_6-18 aryl,

(h) -0-(CH₂VSO₂-(CH₂VOH,

(i) -O-(CH₂)_n-NR⁸-SO₂-(optionally halogenated C₁₄ alkyl), G) -CO-NR⁸-(CH₂)_n-OH,

(k) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(I) -NR⁶R⁷,

(m) -NR⁸-(CH₂)_n-OH,

(n) -NR⁸-(CH₂)_n-SO₂-Ci₄ alkyl, (o) -NR⁸-CO-(CH₂)_n-OH,

(p) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(q) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl),

(r) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), (s) -NR⁸-CO-(CH₂)_n-SO₂-C₃-₈ cycloalkyl,

(t) -NR⁸-CO₂-(CH₂VSO₂-C₁₄ alkyl,

(u) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(v) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl, 5 (W) -S-(CH₂VOH,

(x) -SO-(CH₂)_n-OH,

(y) -SO₂-(CH₂VOH, and

(z) -NR⁸-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an i o oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C_1-4 alkyl, -

CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R and R⁷ are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R⁸ is a hydrogen atom or a C₁₄ alkyl group, and (CH₂)_n is optionally substituted 15 by C₁₄ alkyl or hydroxy;

R^3a is a hydrogen atom or a C₁^ alkyl group; or

R^la and R²⁸ are optionally bonded to form

R²*¹ and R^3a are optionally bonded to form C₂₄ alkylene, is preferable. 0 Of these, as R²⁸, a C_1-8 alkyl group, a C_2-8 alkenyl group or a C_2-8 alkynyl group (particularly, a C_1-8 alkyl group), each of which is substituted by substituent(s) selected from (a) hydroxy,

(b) optionally halogenated C₁₄ alkyloxy,

(c) -O-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by hydroxy),

(d) -0-(CH₂VO-CO-NH₂, (e) -0-(CH₂VO-C₁₄ alkyl,

(f) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(g) -0-(CH₂VSO₂-C_6-18 aryl,

(h) -0-(CH₂VSO₂-(CH₂VOH,

(i) -0-(CH₂VNR⁸-S0₂-(optiona]ly halogenated C₁₄ alkyl), (j) -CO-NR⁸-(CH₂)_n-OH,

(k) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

(1) -NR⁶R⁷,

(m) -NR⁸-(CH₂)_n-OH,

(n) -NR⁸-(CH₂VSO₂-C₁₄ alkyl, (o) -NR⁸-CO-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(p) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(q) -NR⁸-CO-(CH₂VSO-(optionally halogenated C₁₄ alkyl),

(r) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl), (s) -NR⁸-CO-(CH₂)_n-SO₂-C₃-₈ cycloalkyl,

(t) -NR⁸-CO₂-(CH₂VSO_rC₁₄ alkyl,

(u) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(v) -NR⁸-SO₂-(CH₂)_n-SO₂-C₁₄ alkyl, (W) -S-(CH₂VOH, (X) -SO-(CH₂VOH, (y) -SO₂-(CH₂VOH, and

(z) -NR⁸-CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, C₁₄ alkyl, optionally oxidized CM alkylthio, -CO-C₁₄ alkyl, - CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R and R are the same or different and each is a hydrogen atom or a C₁₄ alkyl group, R is a hydrogen atom or a C₁₄ alkyl group, is preferable. As R²*¹, (i) a C₅-_S alkyl group substituted by hydroxy,

(ii) a C_1-8 alkyl group substituted by substituent(s) selected from

(a) halogenated C₁₄ alkyloxy,

(b) -0-(CH₂VOH, (c) -0-(CH₂VO-CO-NH₂,

(d) -O-(CH₂)_n-O-(optionally halogenated C₁₄ alkyl),

(e) -O-(CH₂VSO₂~(optionally halogenated C₁₄ alkyl), (f) -0-(CH₂)H-SQ₂-C₆-I₈ atyl,

(i) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), O) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl,

(k) -NR⁸-CO-(CH₂)_n-OH, (1) -NR⁸-CO-(CH₂)_n-O-C₁₄ alkyl,

(m) -NR⁸-CO-(CH₂)_n-SO-(optionally halogenated C₁₄ alkyl), (n) -NR⁸-CO-(CH₂)_n-SO₂-(optionalry halogenated C₁₄ alkyl), (o) ~NR⁸-CO-(CH₂)_n-SO₂-C_3-8 cycloalkyl, 5 (P)

alkyl, (q) -NR^CO-NH-(CH₂VSO₂-C₁₄ alkyl, (r) -NR⁸-SO₂-(CH₂)n-SO₂-C₁₄ alkyl, (S) -S-(CH₂VOH, (t) -SO-(CH₂VOH, i o (u) -SO₂-(CH₂VOH, and

(v) -NR -CO-(optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, Ci₄ alkyl, optionally oxidized C₁₄ alkylthio, -CO-C₁₄ alkyl, - is CO-NH-Ci₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-C₁₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, R⁸ is a hydrogen atom or a C₁₄ alkyl group, and (CH₂)_n is optionally substituted by C₁₄ alkyl or hydroxy, (iϋ) a C_2-8 alkenyl group optionally substituted by hydroxy, or (iv) a C_2-8 alkynyl group optionally substituted by hydroxy is preferable, and particularly, 0 as R^2a, (i) a C₅-₈ alkyl group substituted by hydroxy,

(ϋ) a Ci-8 alkyl group substituted by substituent(s) selected from

(a) halogenated Ci₄ alkyloxy,

(b) -O-(CH₂)_n~OH (wherein (CH₂)_n is optionally substituted by hydroxy), (c) -O-(CH₂)_n-O-CO-NH₂,

(d) -O-(CH₂)_n-O-(optionally halogenated CM alkyl),

(e) -O-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl), (f) -0-(CH₂VSO₂-C_6-18 aryl,

5 (g) -O-(CH₂VNR⁸-SO₂-(optionally halogenated C_1-4 alkyl),

(h) -CO-NR⁸-(CH₂VOH,

(i) -CO-NR⁸-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl),

Q) -NR⁸-(CH₂)_n-SO₂-C₁₄ alkyl,

(k) -NR⁸-CO-(CH₂)_n-OH (wherein (CH₂)_n is optionally substituted by Cj₄ alkyl), i o (1) -NR⁸-CO-(CH₂VO-C₁₄ alkyl,

(m) -NR⁸-CO-(CH₂VSO-(optionally halogenated C₁₄ alkyl),

(n) -NR⁸-CO-(CH₂)_n-SO₂-(optionally halogenated C₁₄ alkyl) (wherein (CH₂)_n is optionally substituted by C₁₄ alkyl),

(o) -]NR⁸-CO-(CH₂VSO₂-C₃.₈ cycloalkyl, is (p) -NR⁸-CO₂-(CH₂VSO₂-C₁₄ alkyl,

(q) -NR⁸-CO-NH-(CH₂)_n-SO₂-C₁₄ alkyl,

(r) -NR⁸-SO₂-(CH₂)_n-SO₂-Ci₄ alkyl,

(S) -S-(CH₂VOH,

(t) -SO-(CH₂VOH, 0 (U) -SO₂-(CH₂VOH, and

(v) -NR -CO-(optionaUy substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to 8-membered heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and an optionally oxidized sulfur atom, which is optionally substituted by substituent(s) selected from hydroxy, CM alkyl, optionally oxidized Cμ alkylthio, -CO-CM alkyl, - CO-NH-C₁₄ alkyl, -CONH₂, -SO₂-C₁₄ alkyl, -SO₂-NH-Ci₄ alkyl, -SO₂NH₂ and the like), wherein n is an integer of 1 to 4, and R is a hydrogen atom or a Ci₄ alkyl group, (iϋ) a C_2-8 alkenyl group optionally substituted by hydroxy, or

5 (iv) a C_2-8 alkynyl group optionally substituted by hydroxy is preferable, and as R , a hydrogen atom, methyl, ethyl and the like are preferable, and a hydrogen atom is particularly preferable.

As compound (T), preferred is a compound wherein A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted, wherein Y is a single bond, -0-, -OCH₂-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a i o carbamoyl group, a ureido group, a C_6-I8 aryl-carbonyl group or a C_6-18 aryl-C₁₄ alkyl-carbonyl group, each of which is optionally substituted.

As a preferable embodiment of compound (T), a compound wherein W is C(R¹); A is an aryl group substituted by a group of the formula -Y -B, and optionally further substituted, wherein Y is a single bond, -0-, -OCH₂-, -NH- or -S-, and B is an aryl group, a heterocyclic group,

15 a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-C₁₄ alkyl-carbonyl group, each of which is optionally substituted;

R¹ is a group of the formula -X²-R⁴ wherein X² is a single bond, -NH- or -0-, and R⁴ is hydrogen atom or a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_3-8 cycloalkyl group, a C_6-I8 aryl group, a C_6-I8 aryl-Ci₄ alkyl group, a C_6-I8 0 aryl-carbonyl group, a C_6-I8 aryl-Ci₄ alkyl-carbonyl group, a heterocyclic group, a heterocycle-C₁₄ alkyl group, a heterocycle-carbonyl group or aheterocycle-Ci₄ alkyl-carbonyl group, each of which is optionally substituted;

R² is hydrogen atom or a Ci_-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-C^ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-Cw alkyl-carbonyl group, a C_6-18 aryl-sulfonyl group, a heterocyclic group, aheterocycle-C^ alkyl group, a heterocycle-carbonyl group or aheterocycle-C_M alkyl-carbonyl group, each of which is optionally 5 substituted; and

X¹ is -NR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group can be mentioned.

As another preferable embodiment of compound (T), a compound wherein W is N; X¹ is -NR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbono group;

A is an aryl group substituted by a group of the formula -Y -B and optionally further substituted wherein Y² is a single bond, -O-, -OCH₂-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-Cw alkyl-carbonyl group, each of which is optionally substituted; and s R is a hydrogen atom or a C_1-8 alkyl group, a C_2-8 alkenyl group, a C_2-8 alkynyl group, a carbamoyl group, a C_1-8 alkyl-carbonyl group, a C_1-8 alkylsulfonyl group, a C_3-8 cycloalkyl group, a C_6-18 aryl group, a C_6-18 aryl-C^ alkyl group, a C_6-18 aryl-carbonyl group, a C_6-18 aryl-C^ alkyl- carbonyl group, a C_6-I8 aryl-surfonyl group, a heterocyclic group, aheterocycle-C^ alkyl group, a heterocycle-carbonyl group or aheterocycle-C^ alkyl-carbonyl group, each of which is optionally o substituted can be mentioned.

As a yet another preferable embodiment of compound (T), a compound wherein W is N; X¹ is -NR³-;

A is an aryl group substituted by a group of the formula -Y²-B and optionally further substituted wherein Y² is a single bond, -O-, -OCH₂-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a C_3-8 cycloalkyl group, a carbamoyl group, a ureido group, a C_6-18 aryl-carbonyl group or a C_6-18 aryl-Ci₄ alkyl-carbonyl group, each of which is optionally substituted; and R² and R³ are bonded to form an optionally substituted ring structure can be mentioned. A compound that is an AMPK activator and to be administered to a mammal to protect heart thereof in this method may be N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl}ammo)-5H-pyπolo[3,2-d]pyrirmdin-5-yl]ethyl}-3-hydroxy-3-methylbutanara thereof, or a prodrug thereof.

When compound (T), compound (Ia), compound (Ia'), or N-{2-[4-({3-chloro-4-[3- (1rmuorome1hyl)phenoxy] phenyl} arr^ methylbutanamide has an isomer such as optical isomer, stereoisomer, positional isomer, rotational isomer and the like, any isomers and mixtures of the compound are encompassed in compound (T), compound (Ia), compound (Ia'), orN-{2-[4-({3-chloro-4-[3-(rrifluoromethyl)phenoxy] phenyl} amino)-5H-pyrrolo[3,2-d]pyrirrύdin-5~yl]e^ respectively. For example, when the compound has an optical isomer, an optical isomer separated from aracemate, the optical isomer is also encompassed in compound (T), compound (Ia), compound (Ia'), or N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl} amino)-5H- pyiτolo[3,2-d]pyrrrnidin-5-yl]e1hyl}-3-hydroxy-3-me1hylbutanamide, respectively. These isomers can be obtained as independent products by a synthesis means or a separation means (concentration, solvent extraction, column chromatography, recrystallization and the lrke) known per se.

The compound may be a crystal, and both a single crystal and crystal mixtures, which are encompassed in the compound (T), compound (Ia), compound (Ta'), or N-{2-[4-({3-chloro-4-[3-

(trifluorometlαyl)phenoxy] phenyl} amino)-5H-pyrrolo[3,2-d]pyrirnidin-5--yl]ethyl}-3-hydroxy-3- methylbutanamide, respectively. The crystals can be produced by crystallization according to crystallization methods knomψer se.

The compound may be a solvate (e.g., hydrate etc.) or a non-solvate, both of which are encompassed in the compound (T), compound (Ta), compound (Ia'), orN-{2-[4-({3-chloro-4-[3- (trifluoromethyl)phenoxy] phenyl} amino)-5H-pyrrolo[3 ,2-d]pyrirnidin-5-yl]ethyl} -3 -hydroxy-3 - methylbutanamide, respectively.

The compound labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I and the like) is also encompassed in the compound (T), compound (Ta), compound (Ia'), or N-{2~[4~({3-chloro-4-[3- (trϋluorome1hyl)phenoxy] phenyl} ammo)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydroxy-3- methylbutanamide, respectively.

As the salts of the compounds represented by the compound (T), compound (Ta), compound (Ia'), mdN-{2-[4-({3-cMoro4-[3-(trifiuorome1hyl)phenoxy] phenyl}amino)-5H-pyrrolo[3,2- d]pvrirrύdm-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, for example, metal salt, ammonium salt, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid and the like can be mentioned. As preferable examples of the metal salt, for example, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; aluminum salt and the hike can be mentioned. As preferable examples of the salts with organic base, for example, salts with trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolarnine, triethanolamine, tromethamine [rris(hydroxymethyl)methylamine], t-butylamine, cyclohexylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine and the like can be mentioned. As preferable examples of salts with inorganic acid, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned. As preferable examples of the salts with organic acid, for example, salts with formic acid, acetic acid, trifiuoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like can be mentioned. As preferable examples of the salts with basic amino acid, for example, salts with 5 arginine, lysine, ornithine and the like can be mentioned, and as preferable examples of the salts with acidic amino acid, for example, salts with aspartic acid, glutamic acid and the like can be mentioned.

Of these, pharmaceutically acceptable salts are preferable. For example, when a compound contains an acidic functional group, inorganic salts such as alkali metal salts (e.g., sodium salt, o potassium salt etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, barium salt etc.) and the like, ammonium salt and the like, and when a compound contains a basic functional group, for example, salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, or salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic 5 acid, p-toluenesulfonic acid and the like can be mentioned.

A prodrug of the compounds represented by the compound (T), compound (Ia), compound (Ia'), and N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, or a salt thereof (hereinafter collectively referred to as "the compound in this invention") means a compound that is converted to the o compound in this invention with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the living body, that is, a compound that is converted to the compound in this invention with oxidation, reduction, hydrolysis, etc. according to an enzyme; a compound that is converted to the compound in this invention by hydrolysis etc. due to gastric acid, etc. A prodrug for the compound in this invention may be a compound obtained by subjecting an amino group in the compound in this invention to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in the compound in this invention to an eicosanoylation, danylation, pentylaminocarbonylation, (5-methyl-2-oxo-l,3-αloxolen-4-yl)me1hoxycarbonylation, 5 tetrahydroruranylation, pyrrolidylmethylation, pivaloyloxymethylation and tert-butylation, etc.); a compound obtained by subjecting a hydroxy group in the compound in this invention to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in the compound in this invention to an acetylation, palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, dimethylarninomethylcarbonylation, etc.); a i o compound obtained by subjecting a carboxyl group in the compound in this invention to an esterification or amidation (e.g., a compound obtained by subjecting a carboxyl group in the compound in this invention to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-l,3-dioxolen-4-

15 yl)methyl esterification, cyclohexyloxycarbonylethyl esterification and methylamidation, etc.) and the like. Any of these compounds can be produced from the compound in this invention by a method known per se.

A prodrug for the compound in this invention may also be one which is converted into the compound in this invention under a physiological condition, such as those described in IYAKUHIN 0 no KAIHATSU (Development of Pharmaceuticals}, Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

The compound in this invention, which is the AMPK activator and activates the AMPK, also possesses tyrosine kinase-inhibiting activity and can be used for the prophylaxis or treatment of tyrosine kinase-dependent diseases in mammals. Tyrosine kinase-dependent diseases include diseases characterized by increased cell proliferation due to abnormal tyrosine kinase enzyme activity. However, there are compounds that have the tyrosine kinase-inhibiting activity and may trap transcriptional activators in the nucleus, and these tyrosine kinase inhibitors affect transcription of genes. The compound in this invention does not affect such protein export of the transcriptional activators from nucleus and does not affect the gene transcription. Furthermore, the compound in this invention specifically inhibits EGFR and ErbB2 receptor tyrosine kinase and is therefore also useful as a therapeutic agent for suppressing the growth of ErbB2 and/or EGFRkinase-expressing cancer, or a preventive agent for preventing the transition of hormone-dependent cancer to hormone- independent cancer.

In addition, the compound in this invention is useful in a pharmaceutical composition because it shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity and the like), high water solubility, and is superior in stability, pharmacokinetics (absorption, distribution, metabolism, excretion and the like) and efficacy expression. Accordingly, the compound in this invention can be safely used in a pharmaceutical composition not only for protection of the heart of mammals but also for the prophylaxis or treatment of diseases due to abnormal cell proliferation such as various cancers, atherosclerosis, angiogenesis, and viral diseases, and cardiovascular diseases associated with abnormal tyrosine kinase enzyme activity such as restenosis, (HTV infection etc.). To administer the compound in this invention, which shows high efficacy of heart protection and low toxicity for mammals, the pharmaceutical composition for heart protection for a mammal contains at least one of the compound (1), preferably, at least one of the compound (Ia) or compound (Ia'), orN-{2-[4-({3-chloro-4-[3-(trifiuoromethyl) phenoxy]phenyl} amino)-5H- pvrrolo[3,2-d]pyrimidin-5-yl]ethyl}-3-hydrox^^ a salt thereof, or a prodrug thereof. The pharmaceutical composition can be used in admixture with a commonly known pharmaceutically acceptable carrier etc. in mammals (e.g., humans, horses, bovines, dogs, cats, rats, mice, rabbits, pigs, monkeys, and the like).

5 In addition to the compound in this invention, said pharmaceutical composition may contain other active ingredients, e.g., the following hormonal therapeutic agents, anticancer agent (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors), and the like.

As a pharmaceutical agent for mammals such as humans, the compound in this invention i o can be administered orally in the form of, for example, tablets, capsules (including soft capsules and microcapsules), powders, granules and the like, or parenterally in the form of injections, suppositories, pellets and the like. Examples of the "parenteral administration route" include intravenous, intramuscular, subcutaneous, intra-tissue, intranasal, intradermal, instillation, intracerebral, intrarectal, intravaginal, intraperitoneal, intratumoral, juxtaposition of tumor and

15 administration directly to the lesion.

The dose of the compound in this invention varies depending on the route of administration, a type of a mammal, a type of a heart damages from which the heart is protected, other existing diseases, symptoms, a form of the compound in this invention to be administered, etc. For example, when the compound in this invention is administered orally as to a human patient (body weight 40 to

20 80 kg), its dose is, for example, 0.5 to 100 mg/kg body weight per day, preferably 1 to 50 mg/kg body weight per day, and more preferably 1 or 25 mg/kg body weight per day. This amount may be administered once or in 2 to 3 divided portions daily. The compound in this invention can be safely administered orally or parenteraUy (e.g., topical, rectal, intravenous administrations etc.) as a single agent, or a pharmaceutical composition containing a pharmacologically acceptable carrier according to a conventional method (e.g., a method described in the Japanese Pharmacopoeia etc.), such as tablet (including sugar-coated tablet, 5 film-coated tablet), powder, granule, capsule, liquid, emulsion, suspension, injection, suppository, sustained release preparation, plaster and the like.

And a combination of (1) administering an effective amount of the compound in this invention and (2) 1 to 3 selected from the group consisting of (i) administering an effective amount of anticancer agents, (ϋ) administering an effective amount of hormonal therapeutic agents, (iii) o applying non-drug therapy that can prevent and/or treat cancer more effectively,(iv) administering an effective amount of other therapeutic agents than anticancer agents, or (v) applying non-drug therapy that can prevent and/or treat a target disease other than cancer more effectively can be used. As the non-drug therapy, for example, surgery, radiotherapy, gene therapy, thermotherapy, cryotherapy, laser cauterization, and the like are exemplified and two or more of these may be combined. 5 For example, the compound in this invention can be administered to the same subject simultaneously with hormonal therapeutic agents, anticancer agents (e.g., chemotherapeutic agents, immunotherapeutic agents, or pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors) (hereafter, these are referred to as a concomitant drug) or separately.

The administering of the compound in this invention exhibits excellent heart protection and o can enhance the effectiveness of other therapeutic drugs and/or non-drug therapies when using the compound in this invention in combination with such therapeutic drug(s) and/or non-drug therapy or therapies(multi-agent co-administration). In the present specification, as examples of the "hormonal therapeutic agents" there may be mentioned fosfestrol, diethylstylbestrol, chlorotrianisene, medroxyprogesterone acetate, megestrol acetate, chlormadinone acetate, cyproterone acetate, danazol, dienogest, asoprisnil, allylestrenol, gestrinone, nomegestrol, Tadenan, mepartricin, raloxifene, ormeloxifene, levormeloxifene, anti- ⁵ estrogens (e.g., tamoxifen citrate, toremifene citrate, and the like), ER down-regulator (e.g., fulvestrant (Faslodex (trademark)) and the like), human menopausal gonadotrophin, follicle stimulating hormone, pill preparations, mepitiostane, testrolactone, ammoglutethimide, LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin, and the like), droloxifene, epitiostanol, ethinylestradiol sulfonate, aromatase inhibitors (e.g., fadrozole hydrochloride, anastrozole, retrozole, ° exemestane, vorozole, formestane, and the like), anti-androgens (e.g., flutamide, bicartamide, nilutamide, and the like), 5α-reductase inhibitors (e.g., finasteride, dutasteride, epristeride, and the Hke), adrenocorticohormone drugs (e.g., dexamethasone, prednisolone, betamethasone, triamcinolone, and the like), androgen synthesis inhibitors (e.g., abiraterone, and the like), retinoid and drugs that retard retinoid metabolism (e.g., liarozole, and the like), etc. and LH-RH agonists (e.g., goserelin acetate, buserelin, leuprorelin) and ER down-regulator (e.g., fulvestrant (Faslodex (trademark)) and the like) are preferable.

In the present specification, as the "anti-cancer agent", for example, chemotherapeutic agent, immunotherapeutic agent, a pharmaceutical agent that inhibits the action of cell growth factor and a receptor thereof and the like can be mentioned. As examples of said "chemotherapeutic agents", there may be mentioned alkylating agents, antimetabolites, anticancer antibiotics, plant-derived anticancer agents, and the like.

As examples of "alkylating agents", there may be mentioned nitrogen mustard, nitrogen mustard-N-oxide hydrochloride, chlorambutyl, cyclophosphamide, ifosfamide, thiotepa, carboquone, improsulfantosylate, busulfan, nimustine hydrochloride, mitobronitol, melphalaα, dacarbazine, ranimustine, sodium estramustine phosphate, Iriethylenemelarnine, carmustine, lomustine, streptozocin, pipobroman, etoglucid, carboplatin, cisplatin, miboplatin, nedaplatin, oxaliplatin, altretamine, ambamustine, dibrospidium hydrochloride, fotemustine, prednimustine, ⁵ pumitepa, ribomustin, temozolomide, treosulphan, trophosphamide, zinostatin stimalamer, adozelesin, cystemustine, bizelesin, and the like.

As examples of "antimetabolites", there maybe mentioned mercaptopurine, 6- mercaptopurine riboside, thioinosine, methotrexate, enocitabine, cytarabine, cytarabine ocfosfate, ancitabine hydrochloride, 5-FU drugs (e.g., fluorouracil, tegafur, UFT, doxifluridine, carmo&r, ° gallocitabine, emmitefur, and the like), aminopterine, leucovorin calcium, tabloid, butocine, folinate calcium, levofolinate calcium, cladribine, emitefur, fludarabiαe, gemcitabine, hydroxycarbamide, pentostatin, piritrexim, idoxuridine, mitoguazone, thiazophrine, ambamustine, pemetrexed disodium (Alimta (trademark)) and the like.

As examples of "anticancer antibiotics", there may be mentioned actinomycin-D, actinomycin-C, mitomycin-C, chromomycin-A3 , bleomycin hydrochloride, bleomycin sulfate, peplomycin sulfate, daunorubicin hydrochloride, doxorubicin hydrochloride (Adriacin (trademark)), aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarcomycin, carzinophilin, mitotane, zorubicin hydrochloride, mitoxantrone hydrochloride, idarubicin hydrochloride, and the like. As examples of "plant-derived anticancer agents", there may be mentioned etoposide, etoposide phosphate, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, paclitaxel (Taxol (trademark)), docetaxel, vinorelbine, and the like.

1 lfi As examples of said "immunofherapeutic agents (BRM)", there may be mentioned picibanil, krestin, sizofiran, lentinan, ubenimex, interferons, interleukins, macrophage colony- stimulating factor, granulocyte colony-stimulating factor, erythropoietin, lymphotoxin, BCG vaccine, Corynebacteriumparvum, levamisole, polysaccharide K, procodazole, and the like. 5 As the "growth factor" in said "pharmaceutical agents inhibiting the action of cell growth factors or cell growth factor receptors", there may be mentioned any substances that promote cell proliferation, which are normally peptides having a molecular weight of not more than 20,000 that are capable of exhibiting their activity at low concentrations by binding to a receptor, including (1 ) EGF (epidermal growth factor) or substances possessing substantially the same activity as it [e.g., ° EGF, heregulin, and the like], (2) insulin or substances possessing substantially the same activity as it [e.g., insulin, IGF (insulin-like growth factor)- 1, IGF-2, and the like], (3) FGF (fibroblast growth factor) or substances possessing substantially the same activity as it [e.g., acidic FGF, basic FGF, KGF (keratinocyte growth factor), FGF-10, and the like], (4) other cell growth factors [e.g., CSF (colony stimulating factor), EPO (erythropoietin), IL-2 (interleukin-2), NGF (nerve growth factor), PDGF (platelet-derived growth factor), TGFβ (transformirig growth factor β), HGF (hepatocyte growth factor), VEGF (vascular endothelial growth factor), and the like], and the like.

As examples of said "growth factor receptors", there may be mentioned any receptors capable of binding to the aforementioned growth factors, including EGF receptor, heregulin receptor (HER2), insulin receptor, IGF receptor, FGF receptor- 1 or FGF receptor-2, and the like. As examples of said "pharmaceutical agent that inhibits the action of cell growth factor",

HER2 antibody (trastuzumab (Herceptin (trademark)) etc.), rmatinib mesylate, ZD 1839 or EGFR antibody (cetuximab (Erbitux) (trademark)) etc.), antibody to VEGF (e.g., bevacizumab (Avasth)(trademark)), VEGFR antibody, VEGFR inhibitor, EGFR inhibitor (erlotinib (Tarceva)(trademark)), gefitinib (Tressa (trademark)) etc.) can be mentioned.

In addition to the aforementioned drugs, mTOR inhibitors (temsirolimus, rapamycin, and the like), Akt inhibitors, PB kinase inhibitors, L-asparaginase, aceglatone, procarbazine 5 hydrochloride, protopoφhyrin-cobalt complex salt, mercuric hematoporphyrin-sodium, topoisomerase I inhibitors (e.g., irinotecan hydrochloride (Topotecin (trademark), Campto (trademark), topotecan, and the like), topoisomerase II inhibitors (e.g., sobuzoxane, and the like), differentiation inducers (e.g., retinoid, vitamin D, and the like), angiogenesis inhibitors (e.g., thalidomide, SUl 1248 (Sunitinib), and the like), α-blockers (e.g., tamsulosin hydrochloride, ° naftopidil, urapidil, alfuzosin, terazosin, prazosin, silodosin, and the like) serine/threonine kinase inhibitor, endothelin receptor antagonist (e.g., atrasentan, and the like), proteasome inhibitor (e.g., bortezomib, and the like), Hsp 90 inhibitor (e.g., 17- AAG, and the like), spironolactone, minoxidil, 1 lα-hydroxyprogesterone, bone resorption inhibiting/metastasis suppressing agent (e.g., zoledronic acid, alendronic acid, pamidronic acid, etidronic acid, ibandronic acid, clodronic acid) and the like⁵ can be used.

Of those mentioned above, a hormonal therapeutic agent or anti-cancer agent (hereinafter to be abbreviated as a concomitant drug), ER down-regulator (for example, fulvestrant (Faslodex (trademark)) etc.), HER2 antibody (trastuzumab (Herceptin (trademark)) etc.), EGFR antibody (cetuximab (Erbitux (trademark) etc.), EGFR inhibitor (erlotinib (Tarceva (trademark), gefitinib ° (Iressa (trademark)) etc.), VEGFR inhibitor or a chemotherapeutic agent (paclitaxel (Taxol

(trademark) etc.) is preferable. Particularly, fulvestrant (Faslodex (trademark)), trastuzumab (Herceptin (trademark)), cetuximab (Erbitux (trademark)), erlotinib (Tarceva (trademark)), gefitinib (Iressa (trademark)), paclitaxel (Taxol (trademark)) and the like are preferable.

In addition, doxorubicin hydrochloride (Adriacin (trademark)), irinotecan hydrochloride 5 (Topotecin (trademark), Campto (trademark)), 5FU, docetaxel and methotrexate are among the preferable examples.

In combination of the compound in this invention and the concomitant drug, the administration time of the compound in this invention and the concomitant drug is not restricted, and the compound in this invention and the concomitant drug can be administered to the administration i o subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the administration amount clinically used, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.

The administration mode of the compound in this invention and the concomitant drug is not 15 particularly restricted, and it is sufficient that the compound in this invention and the concomitant drug are combined in administration. Examples of such adrninistration mode include the following methods:

(1) The compound in this invention and the concomitant drug are simultaneously produced to give a single preparation which is administered. (2) The compound in this invention and the concomitant 0 drug are separately produced to give two kinds of preparations which are administered simultaneously by the same administration route. (3) The compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by the same administration route only at the different times. (4) The compound in this invention

1 1 Q and the concomitant drug are separately produced to give two kinds of preparations which are administered simultaneously by different administration routes. (5) The compound in this invention and the concomitant drug are separately produced to give two kinds of preparations which are administered by different administration routes at different times (for example, the compound in this 5 invention and the concomitant drug are administered in this order, or in the reverse order).

An AMP-activated protein kinase (AMPK) of a mammal can be activated by administering a compound that has activity of activating the AMPK to the mammal. In this invention, by administering at least one of the compound (T), compound (Ta), compound (Ia'), or N-{2-[4-({3- cMoro4-[3-(trifluoromethyl)phenoxy] phenyl}a^ i o hydroxy-3-methylbutanamide, a salt thereof, and a prodrug thereof (i.e., the compound in this invention) to a mammal, the AMPK of the mammal is activated. The inventors have found a pharmaceutical composition that includes at least one compound that has the activity of activating the AMPK of a mammal, a salt thereof, or a prodrug thereof, to be administered to a mammal to activate the AMPK thereof and use of at least one compound that has an activity of activating the

15 AMPK of a mammal, a salt thereof, or a prodrug thereof for the pharmaceutical composition to be administered to a mammal to activate the AMPK thereof. The compound (T), compound (Ia), compound (Ia'), N-{2-[4-({3-chloro-4-[3-(trϋluoromethyl)phenoxy] phenyl} amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]e1hyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof (i.e., the compound in this invention) has the activity of activating the AMPK of a mammal. 0 The inventors found pharmaceutical compositions containing at least one of the compound in this invention and use of the compound in this invention in the pharmaceutical composition to be administered to a mammal to activate the AMPK thereof. For the method of activating the AMPK, the pharmaceutical composition for activation the AMPK, and the use of the compounds in this invention for the pharmaceutical composition, additional ingredients, dose, dosage forms, administering routes, combination drugs, administering methods, combination therapies, and others described above for the method of protecting the heart of a mammal in need by administering the AMPK activator, the pharmaceutical composition with the AMPK activator, and use of the 5 compound in this invention for the pharmaceutical composition may apply.

As discussed above, the activated AMPK by the AMPK activator such as the compound in this invention influences metabolic pathways in a way of down regulation, i.e., cessation of metabolism, in cardiac cells of mammals and provides heart protection to the mammals. Activation of AMPK may initiate a series of phosphorylation in downstream that switch cells from an active i o ATP consumption state in which the cells synthesize fatty acid, cholesterol, and protein, etc. to an ATP production state in which the cells use fatty acid and glucose in these cells. As a result, when the AMPK is activated by the AMPK activator such as the compound in this invention, a level of lipids is decreased in the cells. In addition, when the AMPK activator is added to the cardiac cells of mammals and a level of lipids is decreased, it is considered that the AMPK is activated.

15 EXAMPLES

Example 1: Western Blot Analysis

Human primary miocardiocytes (HMCs) were obtained from ScienCell Research Laboratories (San Diego, CA) and cultured in the HMC-specific media provided by the same company on Poly-L-lysine-coated plastic (Costar). The HMCs were treated for one hour with 2.5 0 μM and 25 μM of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy] phenyl} amino)-5H- pyirolo[3,2-d]pyrimidm-5-yl]emyl}-3-hydroxy-3-methylbu1anamide ("Compound"). At the end of treatment, whole cell extracts were generated using Modified RIPA Buffer (50 mM Tris-HCl, pH

7.4; 150 mM NaCl; 1%NP-4O; 1 mM EDTA) plus protease inhibitors (PMSF, Leupeptin, Aprotinin, Pepstatin) and phosphatase inhibitors (Phosphogaurd ), quantified for protein content by Lowry Assay (DC Protein Assay, Biorad) and stored at -7O⁰C until use. Western Blot analysis was performed on the LI-COR Odyssey according to manufacturer's instructions. In brief, equal amounts of total protein were electrophoresed on a SDS-denaturing polyacrylamide gel, transferred 5 to PVDF membranes (Millipore) and blotted using the following primary antibodies: p-Akt, p- Erkl/2, p-AMPKα, p-NF-κB, p-ACC and p-eEF2 (Cell Signaling). Secondary antibodies were either DRDye^® 680 Conjugate Goat Anti-Rabbit IgG (LI-COR) or IRDye^® 800CW Conjugated Goat Anti-Mouse IgG (LI-COR).

The Compound is one type of compound (T) and simultaneously, one type of compoundo (Ia). The Compound is a tyrosine kinase inhibitor and shows EGRF/ErbB inhibitory activities. Comparative Example 1: Western Blot Analysis

(a) The HMCs were treated in the same way as that in Example 1 except that the HMCs are treated with 2.5 μM and 25 μM of GW 2974 (N⁴^l -Benzyl- lH-indazol-5-yl)-N^, N*- dimethyl-pvrido[3,4-d]pyrmτidme-4,6-diamine) (Sigma) instead of the Compound. 5 (b) The HMCs were treated in the same way as that in Example 1 except that the cells were cultured without adding any drug compound instead of adding the Compound.

(c) The HMCs were treated in the same way as that in Example 1 except that β-actin (anti-rabbit, Cell Signaling; anti-mouse; Sigma) was probed on all Western Blot experiments as an antibody to demonstrate equal sample loading between lanes. o Example 2 : Western Blot Analysis

(a) The HMCs were treated in the same way as that in Example 1 with 25 μM of the Compound except for that only p-AMPKα, p-ACC, p-eEF2, and Actin, instead of p-Akt, p-Erkl/2, p-AMPKα, p-NF-KB, p-ACC, and p-eEF2, were used. (b) The HMCs were treated in the same way as that in Example 2(a) except that the HMCs are treated with 25 μM of Synthesis Example 295. Comparative Example 2: Western Blot Analysis

(a)-(e) The HMCs were treated in the same way as that in Example 2(a) except that the 5 HMCs are treated with 25 μM of Sunitinib (N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2- dihydro-2-oxo-3H-indol-3-ylidine)memyl]-2,4-dimemyl-lH-pyrrole-3-carboxarnide) (LC Laboratories), GW 2974 , Lapatinib (N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2- memylsuh%nylethylarriino)methyl]-2-furyl]quinazohΩ-4-arnin (LC Laboratories), Erlotinib (N-(3- ethynylphenyl)-6,7-bis(2-me1hoxye1hoxy)-4-quinazorinamine, monohydrochloride), and dimethyl i o sulfoxide (DMSO), respectively. Example 3: Western Blot Analysis

(a) The HMCs were treated in the same way as that in Example 1 with 25 μM of the Compound except for that only pp70SK6, PGSK3β(Ser9), p-Akt, and Actin were used.

(b) The HMCs were treated in the same way as that in Example 3 (a) except that the 15 HMCs are treated with 25 μM of Synthesis Example 295.

Comparative Example 3: Western Blot Analysis

(a)-(e) The HMCs were treated in the same way as that in Example 3 (a) except that the HMCs are treated with 25 μM of Sunitinib, GW 2974 , Lapatinib, Erlotinib, and DMSO, respectively. 0 Results

As shown in Fig. 1 , the treatment of HMCs with the Compound results in AMPK activation shown by increased p-ACC. Activation of the survival factor NF-κB is also observed in the HMCs treated with the Compound (see Fig. 1). The treatment of HMCs with the Compound also shows decrease of p-Akt and p-Erkl/2 in Fig. 1. However, the HMCs treated with β-actin show no activation of the AMPK nor decrease of p-Akt and p-Erkl/2, and the HMCs treated with GW 2974 do not show sufficient AMPK activation, i.e., increase of p-ACC, which prevents the ATP- consuming mechanism of fatty acid biosyntehsis, and sufficient increase of NF-κB or decrease of p- 5 Akt and p-Erkl/2 as those treated with the Compound (see Fig. 1). When the HMCs are treated with the Comopund, the higher increase of p-eEF2, which shows stronger prevention of the ATP consuming mechanism through protein translation, than that with GW2974 is observed.

As shown in Fig.2, the Compound and Synthesis Example 295 increase in p-ACC that prevents the ATP-consuming mechanism of the fatty acid biosynthesis. Synthesis Example 295 o shows higher increase in p-eEF2 that prevents the ATP-consuming mechanism of protein translation. However, Sunitinib, Lapatinib, and Erlotinib do not demonstrate such inhibition of the ATP-consuming mechanisms of the fatty acid biosynthesis and protein translation.

Further, the Compound and Synthesis Example 295 demonstrate reduction of pp70S6K and thus prevent the ATP-consuming mechanism of protein synthesis (see Fig. 3). The Compound and 5 Synthesis Example 295 show higher reduction of pGSK3 β(Ser9) and thus may prevent the ATP- consuming mechanism of Gluconeogenesis better than other compounds. Example 4: Cardiac Lipid Staining

The HMCs were seeded in Tek Chamber Slides (NUNC) and treated with 5.0 μM of the

Compound for 72 hours. Cells were subsequently fixed in 10% neutral-buffered formalin,

o incubated in a working solution of Oil Red-0 (Sigma) for 30 minutes, differentiated in 60% 2-

Propanol (Sigma), and mounted in Glycerol Gelatin (Sigma). Oil Red-0 stock solution was prepared by dissolving 3 mg/ml w/v in 2-Propanol by heating to 100⁰C with constant stirring.

Working Oil Red-0 solution was prepared by combining 3 parts of stock solution to 2 parts ddH₂O

followed by filtering through a 0.45 μM membrane (Millipore). Photographs were taken at 4OX

magnification using a bright-field microscope (Zeiss).

5 Comparative Example 4: Cardiac Lipid Staining

(a) The HMCs were treated in the same way as that in Example 4 except for the cells were treated with 5.0 μM of GW 2974 instead of the Compound.

(b) The HMCs were treated in the same way as that in Example 4 except for the cells were treated with 5.0 μM of Sunitinib instead of the Compound. o (c) The HMCs were treated in the same way as that in Example 4 except for the cells are treated with 5.0 μM of DMSO instead of the Compound.

Results

The HMCs treated with the Compound demonstrate a reduction in lipids where the HMCs treated with Sunitinib and DMSO show massive lipid accumulation (see Fig. 4). Accordingly, ins the HMCs treated with the Compound, the AMPK is activated by the Compound, and the activation of the AMPK prevents accumulation of lipid in cardiac cells.

Example 5: In vivo Treatment of Sprague Dawley Rats

A set of female Sprague Dawley Rats were fasted for 8 hours prior to treatment. The set of rats received a single dose of the Compound at a concentration of 100 mg/kg IP. Heart tissues were o harvested 8 hours after treatment and sectioned for processing of either organ extracts for Western Blot or lipid staining by Oil RedO. Comparative Example 5: In vivo Treatment of Sprague Dawley Rats

(a) A set of female Sprague Dawley Rats were treated in the same way as that in Example 5 except for that the rats received a single dose of Sunitinib instead of the Compound.

(b) A set of female Sprague Dawley Rats were treated in the same way as that in

5 Example 5 except for that the rats received a single dose of Lapatinib instead of the Compound. GW 2974 is a derivative of Lapatinib.

(c) A set of female Sprague Dawley Rats were treated in the same way as that in Example 5 except for that the rats receive a single dose of DMSO as vehicle control instead of the Compound. i o Heart tissues were harvested 8 hours after treatment and further treated in the same way as that in Example 5.

Results

The rat hearts treated with the Compound result in activation of the AMPK but the rat hearts treated with Sunitinib fail to do so (see Fig. 5). Further, the rat hearts treated with the 15 Compound show reduction of lipid accumulation but the rat hearts treated with Sunitinib or

Lapatinib show massive accumulation of lipids more than those treated with the vehicle (see Fig. 6).

Accordingly, it is confirmed in vitro and in vivo that AMPK in cardiac cells of a mammal is activated by administering the Compound to the mammal and the activation of the AMPK prevents 0 accumulation of lipid in cardiac cells in mammals and protects the heart of the mammal. The present invention is not to be limited in scope by the specific embodiments described above. Any functionally equivalent embodiments including various modifications of the invention such as the compound (T), compound (Ia), and compound (Ta'), salt thereof, and prodrug therof and their phramaceutical compositions that are apparent to those skilled in the art from the description 5 and drawings herein are within the scope of this invention.

SYNTHESIS EXAMPLES

The compounds that are the AMPK activator and/or have properties of activating the AMPK and protecting the heart of mammals in this invention are synthesized and used for ° experiments of by way of the following Reference Synthesis Examples, Synthesis Samples,

Formulation Examples, and Supplemental Experimental Examples but these do not limit the present invention.

The elution in column chromatography in Reference Synthesis Examples and Synthesis Examples was performed under observation by TLC (thin-layer chromatography). In the TLC 5 observation, Kieselgel 60F₂₅₄ plate (Merck) or NH TLC plate manufactured by Fuji Silysia Chemical Ltd. was used as a TLC plate, the solvent used as an elution solvent in the column chromatography was used as a developing solvent, and the means of detection used was an UV detector. As silica gel for column, Kieselgel 60F₂S₄ (70-230 mesh) manufactured by Merck or Chromatorex NH DM1020 (basic silica gel, 100-200 mesh) manufactured by Fuji Silysia Chemical o Ltd. was used. The ratio of solvents in silica gel chromatography is a volume ratio of the solvents mixed. In addition, % means percentage by weight unless otherwise specified.

NMR spectra are shown by proton NMR with tetramethylsilane as the internal standard, using VARIAN Gemini-200 (200 MHz type spectrometer) or Gemini-300 (300 MHz type spectrometer) or BRUKER AVANCE300 (300 MHz type spectrometer); δ values are expressed in ppm.

The abbreviations used in Reference Synthesis Examples and Synthesis Examples mean the following:

5 s: singlet, br: broad, d: doublet, t: triplet, q: quartet, dd: double doublet, m: multiplet, J: coupling constant, Hz: hertz, DMSO: dimethyl sulfoxide

Genetic manipulation methods described in Supplemental Experimental Examples below are based on the methods described in Maniatis et al., Molecular Cloning, Cold Spring Harbor Laboratory, 1989, and the appended protocol. i o Reference Synthesis Example 1

Production of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile

To a solution of 2-chloro-4-nitrophenol (3.5 g) and 2-(bromomethyl)benzonitrile (4.0 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (3.7 g), and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, water (50 mL) was 15 added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration. The residue was washed with dϋsopropyl ether, and dried to give the title compound (5.04 g) as pale-yellow crystals.

¹H-NMR (CDCl₃) δ 5.44 (2H, s), 7.13 (IH, d, J= 9.0 Hz), 7.51 (IH, dt, J= 1.2, 7.2 Hz), 7.68-7.80 (3H, m), 8.19 (IH₅ dd, J= 2.7, 9.0 Hz), 8.35 (IH, d, J= 2.7 Hz). 0 Reference Synthesis Example 2

Production of 2-[(4-amrno-2-chlorophenoxy)methyl]benzonitrile

To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile (2.0 g) in ethanol/water

(9: 1 , 40 mL) was added calcium chloride (90%, 427 mg), and the mixture was stirred at 100⁰C for 10 min. Reduced iron (90%, 2.6 g) was added at room temperature, and the mixture was stirred at

100⁰C for 3 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:methylene chloride =2: 1 : 1) to give the title compound (1.2 g) as a white solid.

¹H-NMR (CDCl₃) δ 3.53 (2H, br s), 5.23 (2H, s), 6.54 (IH₃ dd, J= 2.7, 8.7 Hz), 6.76 (IH, d, J= 2.7

Hz), 6.88 (IH, d, J= 8.7 Hz), 7.42 (IH, dt, J= 0.9, 7.8 Hz), 7.62-7.70 (2H, m), 7.81 (IH, d, J= 7.8 Hz).

Reference Synthesis Example 3

Production of 2-[(2-methyl-4-nitrophenoxy)methyl]benzonitrile

The title compound (8.2 g) was obtained as a pale-yellow solid by the reaction in the same manner as in Reference Synthesis Example 1 using 2-methyl-4-nitrophenol (5.0 g) and 2- (bromomethyl)benzonitrile (6.4 g).

¹H-NMR (CDCl₃) δ 2.37 (3H, s), 5.36 (2H, s), 6.97 (IH, d, J= 8.4 Hz), 7.50 (IH, m), 7.65-7.69 (2H, m), 7.76 (IH, td, J= 0.9, 7.5 Hz), 8.09-8.14 (2H, m).

Reference Synthesis Example 4

Production of 2-[(4-amino-2-methylphenoxy)methyl]benzonitrile The title compound (3.7 g) was obtained as a white solid by the reaction in the same manner as in Reference Synthesis Example 2 using 2-[(2-methyl-4- nitrophenoxy)methyl]benzonitrile (6.0 g), calcium chloride (90%, 1.3 g) and reduced iron (90%, 8.3 g)- ¹H-NMR (CDCl₃) δ 2.24 (3H, s), 3.41 (2H, br s), 5.17 (2H, s), 6.48 (IH, dd, J=3.0, 8.4 Hz), 6.56 (IH, d, J= 3.0 Hz), 6.73 (IH, d, J= 8.4 Hz), 7.40 (IH, dt, J= 1.2, 7.5 Hz)₅7.59-7.71 (3H, m). Reference Synthesis Example 5 Production of 3-(2-chloro-4-nitrophenoxy)benzonitrile

5 To a solution of 2-chloro-l-fluoro-4-nitrobenzene (3.7 g) and 3-hydroxybenzonitrile (2.5 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (4.4 g), and the mixture was stirred at 60°C for 4 hrs. After the completion of the reaction, water (50 mL) was added, and the mixture was stirred for 10 min. The resultant pale-yellow solid was collected by filtration, washed with dϋsopropyl ether, and dried to give the title compound (5.3 g) as pale-yellow crystals. i o ¹H-NMR (CDCl₃) δ 7.03 (IH, d, J= 9.0 Hz), 7.27-7.33 (2H, m), 7.55-7.56 (2H, m), 8.15 (IH, dd, J= 2.7, 9.0 Hz), 8.42 (IH₅ d, J= 2.7 Hz). Reference Synthesis Example 6 Production of 3 -(4-arnino-2-chlorophenoxy)benzonitrile

To a solution of 3-(2-chloro-4-nitrophenoxy)benzonitrile (2.0 g) in ethanol/water (9:1, 40 i 5 mL) was added calcium chloride (90%, 449 mg), and the mixture was stirred at 100⁰C for 10 min. Reduced iron (90%, 2.7 g) was added at room temperature, and the mixture was stirred at 100°C for 5 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried 0 over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3 : 1) to give the title compound (1.25 g) as a white solid.

¹H-NMR (CDCl₃) δ 3.75 (2H, br s), 6.60 (IH, dd, J= 2.7, 8.4 Hz), 6.80 (IH, d, J= 2.7 Hz), 6.92 (IH, d, J= 8.4 Hz), 7.06 (IH, m), 7.14 (IH, m), 7.30 (IH, td, J= 1.2, 7.5 Hz), 7.37 (IH, d, J= 7.5 Hz). Reference Synthesis Example 7 Production of ethyl 2-fluoro-5-nitrobenzoate

Under ice-cooling, thionyl chloride (8.02 mL) was added dropwise to ethanol (200 mL), and 2-fluoro-5-nitrobenzoic acid (13.81 g) was added. This mixture was stirred at 80°C for 4 hrs. and concentrated under reduced pressure. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.77 g) as a pale-yellow oil. 1H-NMR (CDCl₃) δ: 1.43 (3H, t, J= 7.2 Hz), 4.46 (2H, q, J= 7.2 Hz), 7.32 (IH, t, J= 9.1 Hz), 8.41 (IH, ddd, J= 9.1, 4.3, 3.0 Hz), 8.85 (IH, dd, J= 6.1, 3.0 Hz). Reference Synthesis Example 8 Production of ethyl 5-amino-2-phenoxybenzoate

A mixture of ethyl 2-fluoro-5-nitrobenzoate (1.07 g), phenol (565 mg), potassium carbonate (1.38 g) and N,N-dimethylformamide (20 mL) was stirred at 80°C for 4 hrs. The reaction mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80 —> 30:70). The object fraction was concentrated under reduced pressure and ethanol (20 mL) and 10% palladium on carbon (1.5 g) were added to the residue (1.54 g). The mixture was stirred overnight under a hydrogen stream. The catalyst was filtered off, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=20:80 -> 50:50) and recrystallized from dϋsopropyl efher-hexane to give the title compound (1.07 g) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 1.12 (3H, t, J= 7.2 Hz), 3.71 (2H, s), 4.17 (2H, q, J= 7.2 Hz), 6.80-6.87 (3H, m), 6.91 (IH, d, J= 8.5 Hz), 6.97 (IH, t, J= 7.3 Hz), 7.21-7.30 (3H, m). 5 Reference Synthesis Example 9

Production of methyl 4-{[7-(memyl1hio)-lH-pyrazolo[4,3-d]pyriniidin-l-yl]methyl}benzoate and methyl 4-{[7-(me1hyltMo)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}berizoate

To a solution of 7-(methylMo)-lH-pyrazolo[4,3-d]pyrimidine (400 mg) inN,N- dixnethylformamide (8 mL) was added 60% sodium hydride (98 mg) under ice-cooling, and the i o mixture was stirred at room temperature for 10 min. Then, methyl 4-(bromomethyl)benzoate (606 mg) was added under ice-cooling, and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column is chromatography (hexane:ethyl acetate=2:l -» 1:2) to give methyl 4- {[7-(methylthio)- IH- pyrazolo[4,3-d]pyrirnidin-l-yl]methyl}benzoate (251 mg) and methyl 4-{[7-(methylthio)-2H- pyrazolo[4,3-d]pyrirnidin-2-yl]methyl}benzoate (450 mg) both as pale-yellow solids, methyl 4-{[7-(me%lthio)-lH-pyrazolo[4,3-d]pyrimidin-l-yl]methyl}benzoate: ¹H-NMR (CDCl₃) δ 2.71 (3H, s), 3.89 (3H, s), 5.93 (2H, s), 7.22 (2H, d, J= 8.1 Hz), 7.98 (2H, d, J= 8.1 Hz), 8.23 (IH, 0 s), 8.80 (IH, s). methyl 4-{[7-(me%ltHo)-2H-pyrazolo[4,3-d]pyrMdin-2-yl]methyl}benzoate: ¹H-NMR (CDCl₃) δ 2.73 (3H, s), 3.92 (3H, s), 5.69 (2H, s), 7.34 (2H, d, J= 8.4 Hz), 8.03 (2H, d, J= 8.4 Hz), 8.04 (IH, s), 8.73 (IH, s). Reference Synthesis Example 10

Production of 2-[7-(methyliMo)-lH-pyrazolo[4,3-d]pyrimidin-l-yl]efhyl benzoate and 2-[7- (methylthio)-2H-pyrazolo [4,3 -d]pyrknidin-2-yl] ethyl benzoate

To a solution of 7-(methyliMo)-lH-pyrazolo[4,3-d]pyrimidine (300 mg) and 2-iodoethyl 5 benzoate (548 mg) in N,N-dimethylformamide (10 mL) was added potassium carbonate (374 mg), and the mixture was stirred at 60°C for 1 hr. After the completion of the reaction, water was added to the reaction mixture. The mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column i o chromatography (hexane:ethyl acetate=3 :2) to give 2-[7-(methyltMo)-lH-pyrazolo[4,3-d]pyrimidin- l-yl]ethyl benzoate (266 mg) and 2-[7-(memyliMo)-2H-pyra2»lo[4,3-d]pyrimidin-2-yl]ethyl benzoate (191 mg) both as pale-yellow solids.

2-[7-(me%l1hio)-lH-pyrazolo[4,3-d]pyriraidin-l-yl]e1hyl benzoate: ¹H-NMR (CDCl₃) δ 2.66 (3H, s), 4.78 (2H, t, J= 5.4 Hz), 5.06 (2H, t, J= 5.4 Hz), 7.27-7.40 (2H, m), 7.53 (IH, m), 7.85-7.89 (2H, is m), 8.20 (IH, s), 8.79 (IH, s).

2-[7-(me%ltMo)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]ethyl benzoate: ¹H-NMR (CDCl₃) δ 2.73 (3H, s), 4.80-4.86 (4H, m), 7.40-7.46 (2H, m), 7.58 (IH, m), 7.94-7.97 (2H, m), 8.20 (IH, s), 8.73 (IH, s). Reference Synthesis Example 11 Production of 3-[7-(methyltMo)-lH-pyrazolo[4₅3-d]pyrimidin-l-yl]propyl benzoate and 3-[7- 0 (methyltWo)-2H-pyrazolo[4,3-d]pyrirnidin-2-yl]propyl benzoate

3-[7-(Me%lthio)-lH-pyrazolo[4,3-d]pyrirnidin-l--yl]propyl benzoate (623 mg) and 3-[7- (memyltMo)-2H-pvrazolo[4,3-d]pyrirnidin-2-yl]propyl benzoate (556 mg) were obtained both as pale-yellow solids by the reaction in the same manner as in Reference Synthesis Example 10 using 7-(me1hylthio)-lH-pyrazolo[4,3-d]pyrimidine (600 mg), 3-iodopropyl benzoate (1.15 g) and potassium carbonate (748 mg).

3-[7<methylthio)-lH-pyrazolo[4,3-d]pyrimidin-l-yl]proρyl benzoate: ¹H-NMR (CDCl₃) δ 2.40- 2.47 (2H, m), 2.66 (3H, s), 4.42 (2H, t, J= 5.7 Hz), 4.88 (2H, t, J= 7.2 Hz), 7.42-7.46 (2H, m), 7.57 (IH, m), 7.98-8.02 (2H, m), 8.15 (IH, s), 8.73 (IH₅ s).

3-[7-(me%liMo)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]propyl benzoate: ¹H-NMR (CDCl₃) δ 2.52- 2.58 (2H, m), 2.72 (3H, s), 4.39 (2H, t, J= 6.0 Hz), 4.65 (2H, t, J= 6.9 Hz), 7.40-7.46 (2H, m), 7.57 (IH, m), 7.96-8.02 (2H, m), 8.14 (IH, s), 8.71 (IH, s). Synthesis Example 1

Production of N-{3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrinτidin-4-amine hydrochloride

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (770 mg) and 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (2.52 g) were dissolved in l-methyl-2-pyrrolidone (10 mL), and the mixture was stirred with heating at 140°C for 2.5 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (300 mL), and stirred at room temperature for 1 hr. The precipitated powder was collected by filtration, washed with ethyl acetate (30 mL), and dried under reduced pressure to give the title compound (1.62 g). Η-NMRCDMSO-dβ) δ: 5.27 (2H, s), 6.63 (IH, d, J= 3 Hz), 7.0-7.5 (5H, m), 7.78 (IH, dd, J= 3 Hz,9 Hz), 8.00 (IH, m), 8.15 (IH, d, J= 3 Hz), 8.79 (IH, s), 11.79 (IH, br s).

Synthesis Example 2

Production of (4-{[4-({3-cHoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- 5 d]pyrimidin-5-yl]methyl}phenyl)methanol

(i) Production of {4-[(4-cMoro-5H-pyrrolo[3,2-d]pyrirrdα%-5-yl)me1hyl]phenyl}methanol

4-Cbloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg) was dissolved in N,N-dimethylformamide

(2 mL), potassium carbonate (304 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Hydroxymethylbenzyl chloride (377 mg) was added, and the mixture was stirred at i o room temperature for 16 hrs. After diluting with water (30 mL), the mixture was extracted with ethyl acetate/tetrahydrofuran (3 : 1 , 80 mLx2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 0:100) to give the title compound

(383 mg) as a powder. is ¹H-NMR(CDCl₃) δ: 2.15 (IH, br s), 4.69 (2H, d, J= 4 Hz), 5.71 (2H, s), 6.76 (IH, m), 7.06 (2H, d,

J= 8 Hz), 7.34 (2H, d, J= 8 Hz), 7.50 (IH, d, J= 3 Hz), 8.69 (IH, s).

(ϋ) Production of (4- { [4-( {3-chloro-4-[(3 -fluorobenzyl)oxy]phenyl} amino)-5H-pyrrolo [3 ,2- d]pyrimidin-5-yl]methyl}phenyl)methanol

{4-[(4-CUoro-5H-pyiτolo[3,2-d]pyrimidin-5-yl)methyl]phenyl}methanol (354 mg) and 3- chloro-4-[(3-fluorobenzyl)oxy]aniline (488 mg) were dissolved in l-methyl-2-pyrrolidone (2.58 mL), and the mixture was stirred with heating at 140°C for 2 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (80 mL) and partitioned with saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was washed with 5 saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -» 0:100) to give the title compound (588 mg) as a powder. 1H-NMR (CDCl₃) δ: 4.77 (2H, s), 5.07 (2H, s), 5.52 (2H, s), 6.26 (2H₅ s), 6.64 (IH, d, J= 3 Hz), 6.81 (IH, d, J= 9 Hz), 6.9 - 7.4 (8H, m), 7.49 (2H, d, J= 8 Hz), 8.44 (IH, s). i o Synthesis Example 3

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3,4-dimethoxybenzoyl)-5H- pyrrolo[3,2-d]pyrimidin-4-amine

Under ice-cooling, to a suspension of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-5 pyrrolo[3,2-d]pyrimidin-4-amine hydrochloride (150 mg) and potassium carbonate (102 mg) in N,N-dimethylformamide (1.5 mL) was added 3,4-dimethoxybenzoyl chloride (82 mg), and the mixture was stirred under ice-cooling, for 1 hr. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 — > ethyl acetate:methanol=80:20), and crystallized from diisopropyl ether to give the title compound (104 mg)-

¹H-NMR(CDCl₃) δ: 3.97 (3H, s), 4.01 (3H, s), 5.14 (2H, s), 6.72 (IH, d, J= 3 Hz), 6.9-7.6 (1OH, m), 7.88 (2H₅ d, J= 3 Hz), 8.63 (IH, s), 9.75 (IH, br s).

Synthesis Example 4

Production of (4-{[4-({3-me1hyl-4-[(6-me1hylpyridm-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirrύdin-5-yl]methyl}phenyl)methanol

The title compound (242 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 2 (ii) using {4-[(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)methyl]phenyl}methanol (200 mg), 3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]aniIine (235 mg) and 1 -methyl-2-pyrrolidone (1.46 mL). 1H-NMR(CDCl₃) δ: 2.14 (3H, s), 2.50 (3H, s), 3.01 (IH, br s), 4.75 (2H, s), 5.53 (2H, s), 6.38 (IH, br s), 6.64 (IH, d, J= 3 Hz), 6.75 (IH, d, J= 9 Hz), 6.8-7.2 (6H, m), 7.34 (2H, d, J= 3 Hz), 7.47 (IH, d, J= 9 Hz), 8 09 (IH, m), 8.46 (IH, s). Synthesis Example 5

Production of N-{3-me1hyl-4-[(6-methylpyridin~3~yl)oxy]ph^^ amine

The title compound (283 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 2 (ii) using 4-chloro-5H-pyrrolo [3 ,2-d]pyrimidine (200 mg), 3 -merhyl-4- [(6-me1hylpyridin-3-yl)oxy]aniline (418 mg) and l-methyl-2-pyrrolidone (2.6 mL). 1H-NMR (CDCl₃) δ: 2.16 (3H, s), 2.51 (3H, s), 6.56 (IH, d, J= 3 Hz), 6.80 (IH, d, J= 9 Hz), 7.0-7.6 (5H, m), 8 17 (IH, m), 8.59 (IH, s), 8.76 (IH, br s), 11.08 (IH, br s). Synthesis Example 6

Production of methyl 4-{[4-({3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}benzoate

(i) Production of methyl 4-[(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)methyl]benzoate

The title compound (1.0 g) was obtained as a powder by the reaction in the same manner as in Synthesis Example 2 (i) using 4-cWoro-5H-pyiτolo[3,2-d]pyrirnidine (710 mg), methyl A-

(bromomethyl)benzoate (1.27 g), potassium carbonate (703 mg) andN,N-dimethylformamide (9.2 mL).

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 5.77 (2H, s), 6.83 (IH, d, J= 3 Hz), 7.08 (2H, d, J= 8 Hz), 7.53 (IH, d, J= 3 Hz), 8.00 (2H, d, J= 8 Hz), 8.73 (IH₅ s).

(ϋ) Production of methyl 4-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}benzoate

The title compound (1.35 g) was obtained as a powder by the reaction in the same manner as in Synthesis Example 2 (ii) using methyl 4-[(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)methyl]benzoate (1.0 g), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (1.25 g) and l-methyl-2- pyrrolidone (6.63 mL). 1H-NMR (CDCl₃) δ: 3.93 (3H, s), 5.07 (2H, s), 5.57 (2H, s), 6.10 (2H, br s), 6.68 (IH, d, J= 3 Hz), 6.7-7.4 (1OH, m), 8.11 (2H, d, J= 9 Hz), 8.47 (IH, s). Synthesis Example 7

Production of 4-{[4-({3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}benzoic acid

Me&yl 4-{[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}benzoate (850 mg) was dissolved in a mixed solvent of ethanol (3.29 mL)/tetrahydrofuran (3.29 mL), IN aqueous sodium hydroxide solution (3.29 mL) was added, and the mixture was stirred at room temperature for 20 hrs. IN Hydrochloric acid (3.29 mL) was added to the reaction mixture and the mixture was diluted with water (20 mL). The precipitated crystals were coEected by filtration, washed with water (10 mL), and dried under reduced pressure to give the title compound (738 mg).

¹H-NMR (DMSO-de) δ: 5.21 (2H, s), 5.94 (2H, s), 6.62 (IH, d, J= 3 Hz), 7.0 - 7.6 (9H, m), 7.84 (2H, d, J= 9 Hz), 7.91 (IH, d, J= 3 Hz), 8.40 (IH, s), 8.81 (IH, br s), 12.88 (IH, br s). Synthesis Example 8

Production of l-(4-{[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]methyl}benzoyl)piperidin-4-ol

To aniix1ure of4-{[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}anτMo)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]methyl}benzoic acid (150 mg), 4-hydroxypiperidine (33.2 mg) and 1- hydroxybenzotriazole monohydrate (60 mg) inN,N-dimethylformamide (3 mL) were added 1- ethyl-3-(3-dime1hylaminopropyl)carbodiirnide hydrochloride (86 mg) andtriethylamine (0.208 mL) at room temperature and the mixture was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (50 mL) and water (30 mL). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > ethyl acetate:methanol=80:20), and crystallized from diisopropyl ether to give the title compound (168 mg). ¹H-NMR (CDCl₃) δ: 1.4-2.1 (5H, m), 3.0-3.7 (3H, m), 3.97 (IH, m), 4.16 (IH, m), 5.08 (2H, s), 5.55 (2H, s), 6.33 (IH, br s), 6.66 (IH, d, J= 3 Hz), 6.82 (IH, d, J= 9 Hz), 6.9-7.5 (1 IH, m), 8.47 (IH, s).

Synthesis Example 9

Production of 6-(3 -arninophenyl)-N- {3 -methyl-4- [(6-methylpyridin-3-yl)oxy]phenyl} -5H- pyrrolo[3,2-d]pyrimidin-4-amine

(i) Production of 6-cUoro-N-{3-me&yl~4-[(6-me1hylpyridi^ amine hydrochloride i o 4,6-Dichloro-5-nitropyrimidine (9.7 g) was dissolved in l-methyl-2-pyrrolidone (25.7 mL), a solution of 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (5.35 g) in l-methyl-2-pyrrolidone (10 mL) was added dropwise under cooling at -15°C, and the mixture was stirred at -1O⁰C to 0°C for 1 hr. The mixture was diluted with ethyl acetate (100 mL) and stirred at 0⁰C for 15 min. The precipitated crystals were collected by filtration, washed with ethyl acetate (30 mL), and dried under 15 reduced pressure to give the title compound (7.34 g).

¹H-NMR (DMSOd₆) δ: 2.20 (3H₅ s), 2.67 (3H, s), 7.0-8.0 (5H, m), 8.44 (IH, m), 8.55 (IH, s),

10.14 (IH, br s).

(ii) Production of 6-cMoro-N4-{3-me1h^yl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrirnidine-4,5- diamine 0 6-CUoro-N-{3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}-5-ritropyrimidin-4-amm hydrochloride (2.04 g) was suspended in diethyl ether (9.45 mL) and a solution of tin(TV) chloride dihydrate (9.1 g) in cone, hydrochloric acid (20.17 mL) was added under ice-cooling. After stirring at room temperature for 3 hrs, the reaction mixture was poured into ice water (400 mL). A 50% aqueous sodium hydroxide solution (18 mL) was added dropwise to adjust pH to 8. Ethyl acetate 5 (300 mL) was added and the mixture was filtered through celite. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (1.30 g).

¹H-NMR (CDCl₃) δ: 2.23 (3H, s), 2.52 (3H, s), 6.85 (IH, d, J= 9 Hz), 7.0-7.5 (4H, m), 8.16 (IH, s),

8.21 (IH, d, J= 3 Hz).

(in) Production of 6-iodo-N4-{3-memyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5- i o diamine hydriodide

6-CUoro-N4-{3-memyl-4-[(6-me1hylpvric^

(400 mg) was suspended in 55% hydriodic acid (6.16 mL), sodium iodide (878 mg) was added, and the mixture was stirred with heating at 70⁰C for 10 min. After cooling to room temperature, water

(40 mL)/ethyl acetate (30 mL) was added. After adjusting its pH to not less than 7 with aqueous is sodium hydrogen carbonate, and the mixture was stirred at room temperature for 15 min. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (626 mg).

¹H-NMR(CDCl₃) δ: 2.19 (3H, s), 2.52 (3H, s), 4.23 (2H, br s), 6.81 (IH, d, J= 9 Hz), 7.0-7.5 (5H, m), 7.97 (IH, s), 8.18 (IH, d, J= 3 Hz). 0 (iv) Production of 6-[(3-amiQophenyl)ethynyl]-N4-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}pvrmτidme-4,5-diamine

6-Iodo-N4-{3-me1hιyl-4-[(6-methylpyriα^-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydriodide (200 mg) was dissolved in a mixed solvent of acetonitrile (7.6 mL)/triethylamine (5.72 mL), 3-ethynylaniline (0.0574 niL), trans-dicUorobis(1riphenylphosphine)paUadium(II) (15.4 mg) and copperQ iodide (5.3 mg) were sequentially added, and the mixture was stirred under a nitrogen stream at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure and the residue was separated and purified by silica gel column chromatography (eluent, 5 hexane:ethyl acetate=80:20 -> ethyl acetate:methanol=80:20) to give the title compound (157 mg). 1H-NMR (CDCl₃) δ: 2.19 (3H, s), 2.51 (3H, s), 3.65 (2H₅ br s), 4.37 (2H, br s), 6.6-7.5 (9H, m), 7.50 (IH, br s), 8.19 (IH, d, J= 3 Hz), 8.29 (IH, s).

(v) Production of 6-(3-aminophenyl)-N-{3-me1iiyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine i o 6-[(3-Amiπophenyl)ethynyl]-4-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}pyrimidine-4,5-diamine (140 mg) was dissolved in N,N-dime1hylformamide (0.82 mL), copper(T) iodide (6.3 mg) was added and the mixture was stirred under a nitrogen stream with heating at 110°C for 16 hrs. After cooling to room temperature, the reaction mixture was diluted with dichloromethane (20 mL), and filtered through celite. The filtrate was concentrated under

15 reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 —> 85:15) and crystallized from diisopropyl ether to give the title compound (76 mg).

¹H-NMR (DMSOd₆) δ: 2.22 (3H, s), 2.44 (3H, s), 5.32 (2H, br s), 6.65 (IH, d, J= 7 Hz), 6.76 (IH, d, J= 2 Hz)₅ 6.9-7.3 (6H₅ m), 7.75 (IH₅ dd, J= 3 Hz, 9 Hz), 7.83 (IH, d, J= 2 Hz), 8.18 (IH, d, J= 3 0 Hz)₅ 8.34 (IH₅ s), 9.14 (IH, br s), 11.47 (IH₅ br s). Synthesis Example 10

Production of 6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-arnine

6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)o^ hydriodide (270 mg) was dissolved in a mixed solvent of acetonitrile (10.3 mL)/triethylarnine (7.72 mL), and 4-ethynylaniline (80.3 mg), tratαs-dicMorobis(triphenylphosphine)palladium(ir) (20.8 mg) and copper® iodide (7.16 mg) were sequentially added. The title compound (134 mg) was i o obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).

¹H-NMR (CDCl₃) δ: 2.20 (3H, s), 2.51 (3H, s), 4.00 (4H, br s), 6.60 (2H, d, J= 9 Hz), 6.83 (IH, d,

J= 9 Hz), 7.0-7.5 (6H, m), 8.21 (IH, m), 8.29 (IH, s).

(ϋ) Production of 6-(4-aminophenyl)-N-{3-methyl-4--[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo [3 ,2-d]pyrirrύdin-4-arnine 15 The title compound (68 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using 6-[(4-aminophenyl)ethynyl]-N4-{3-methyl-4-[(6- me1hylpyridin-3-yl)oxy]phenyl}pvrirniα^e-4,5-diamine (160 mg) and copper(T) iodide (7.2 mg).

¹H-NMR (DMSO-dδ) δ: 2.21 (3H, s), 2.44 (3H, s), 5.58 (2H, br s), 6.70 (2H, d, J= 9 Hz), 6.99 (IH, d, J= 2 Hz)₅ 7.20 (2H, m), 7.56 (IH, d, J= 9 Hz), 7.75 (IH, dd, J= 2 Hz, 9 Hz), 7.81 (IH, d, J= 2 Hz), 0 8.18 (IH, d, J= 2 Hz), 8.32 (IH, s), 9.12 (lH,br s), 11.38 (IH, br s). Synthesis Example 11

Production of 2-me1iιoxy-N-{4-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo [3 ,2-d]pyrimidin-6-yl]phenyl} acetamide

5 To amixture of 6-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-

5H-pyrrolo[3,2-d]pyrirnidin-4-amine (40 mg), methoxyacetic acid (0.0145 mL) and 1- hydroxybenzotriazolemonohydrate (38 mg) inN,N-dimethylformamide (1.9 mL) were added 1- emyl-3-(3-dimethylammopropyl)carbodiimide hydrochloride (54 mg) andtriethylamine (0.079 mL) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted i o with dichloromethane (10 mL). The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:methanol=85:15) and crystallized from dϋsopropyl ether to give the title compound (24 mg).

¹H-NMR (DMSOd₆) δ: 2.21 (3H, s), 2.43 (3H, s), 3.39 (3H, s), 4.04 (2H, s), 6.91 (IH, d, J= 2 Hz), 6.99 (IH, d, J= 9 Hz), 7.20 (2H, m), 7.7-7.9 (6H, m), 8.17 (IH, d, J= 3 Hz), 8.33 (IH₅ s), 9.07 (IH, is br s), 9.97 (IH, br s), 11.52 (IH, br s). Synthesis Example 12

Production of 6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyirolo[3₅2-d]pyrimidin-4-amine hydrochloride

(i) Production of 6-(4-methoxyphenyl)-5H-pyrrolo[3₅2-d]pyrknidin-4-ol

Ethyl 3-arnino--5-(4-rnethoxyphenyl)-lH-pyrrole-2-carboxylate (7.2 g) was dissolved in tetrahydrofuran (16 mL)/ethanol (32 mL), formamidine (3.46 g) was added, and the mixture was stirred at 90°C for 16 hrs. After cooling to room temperature, tetrahydrofuran was evaporated under reduced pressure. The residue was diluted with ethanol (20 mL), and the precipitated powder was collected by filtration, washed with ethanol (15 mL) and dried under reduced pressure to give the title compound (769 mg). 1H-NMR (DMSO-Cl₆) δ: 3.80 (3H, s), 6.76 (IH, s), 6.9-7.1 (3H₅ m), 7.7-8.0 (2H, m), 11.83 (IH, br s).

(ϋ) Production of 4-cUoro-6-(4-methoxyphenyl)-5H-pyrrolo[3,2-d]pyrirnidine

6-(4-Methoxyphenyl)-5H-pyrrolo[3,2-d]pyrirnidin-4-ol (500 mg) was suspended in N₅N- diethylanirme (1.11 mL)/l₅2-dichloroethane (3.73 mL), phosphorus oxychloride (2.29 mL) was added, and the mixture was stirred with heating at 110°C for 2 hrs. After cooling to room temperature, the reaction mixture was treated with ice water (20 mL), and adjusted to pH 7 or above with aqueous ammonia After diluting with tetrahydrofuran (500 mL), the mixture was washed with saturated brine (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 20:80) to give the title compound (25 mg).

¹H-NMR (CDCl₃) δ: 3.90 (3H, s), 6.92 (IH, s), 7.05 (2H, d, J= 9 Hz), 7.71 (2H₅ d, J= 9 Hz), 8.73

(IH₅ s).

(iϋ) Production of 6-(4-methoxyphenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-atnine hydrochloride

The title compound (11 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 1 using 4-cMoro-6-(4-me1hoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidine (13 mg), 3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]aniline (16 mg) and l-methyl-2-pyrrolidone (0.2 mL). 1H-NMR (DMSO-d_δ) δ: 2.24 (3H, s), 2.46 (3H, s), 3.86 (3H, s), 7.02 (IH, s), 7.14 (2H, d, J= 9 Hz), 7.26 (2H, m), 7.80 (IH, dd, J- 3 Hz, 9 Hz), 7.90 (IH, d, J= 3 Hz), 8.11 (2H, d, J= 9 Hz), 8.22 (IH, d, J- 3 Hz), 8.72 (IH, s), 11.54 (IH, br s). Synthesis Example 13

Production of (2E)-3-[4-({3-methyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-6-yl]-2-propen- 1 -ol

(i) Production of (2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl } ammo)pyrimidin-4-yl] -2-penten-4-yn- 1 -ol

6-Iodo-N4-{3-memyl-4-[(6-me1hylpyridrn-3-yl)oxy]phenyl}pyrirrύdme4,5-diarnine hydriodide (507 mg) was dissolved in a mixed solvent of acetonitrile (19.4 mL)/triethylamine (14.5 mL), 2-penten-4-yn-l-ol (106 mg), 1ram-dicMorobis(1riphenylphosphine)paUaΛum(Ti) (38.8 mg) and copperQ iodide (13.4 mg) were sequentially added. The title compound (373 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).

¹H-NMR (DMSOd₆) δ: 2.17 (3H, s), 2.43 (3H, s), 4.12 (2H, m), 5.52 (2H, br s), 6.05 (IH, dt, J= 2 Hz, 16 Hz), 6.53 (IH₅ dt, J= 5 Hz, 16 Hz), 6.93 (IH, d, J= 9 Hz), 7.20 (2H, m), 7.63 (2H, m), 7.96 (IH, s), 8.15 (IH, d, J= 3 Hz), 8.57 (IH, br s).

(ϋ) Production of (2E)-3-[4-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyriπiidin-6-yl]-2-propen- 1 -ol

The title compound (59 mg) was obtained by the reaction in the same manner as in Synthesis Example 9 (v) using (2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammo)pyrirnidin-4-yl]-2-penten-4-yn-l-ol (200 mg), copper© iodide (9.8 mg) and N,N-dimethylformamide (1.29 mL), and crystallization from dϋsopropyl ether. 1H-NMR (DMSOd₆) δ: 2.20 (3H, s), 2.43 (3H, s), 4.22 (2H, d, J= 3 Hz), 6.45 (lH,m), 6.50 (IH, s), 6.67 (IH, dt, J= 16 Hz), 6.98 (IH, d, J= 9 Hz), 7.19 (2H, m), 7.72 (IH, dd, J= 3 Hz, 9 Hz), 7.80 (IH, d, J= 2 Hz), 8.17 (IH, d, J= 2 Hz), 8.30 (IH, s), 9.02 (IH, br s), 11.30 (IH, br s). Synthesis Example 14

Production of 6- [3 -(aminomethyl)phenyl] -N- {3 -methyl-4- [(6-methylpyridin-3-yl)oxy]phenyl} -5H- pyrrolo[3,2-d]pyώmdin-4-amine (i) Production of tert-butyl 3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammo)pyrirrύdin-4-yl]ethynyl}benzylcarbamate

6-Iodo-N4-{3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidme4,5-diamine hydriodide (500 mg) was dissolved in amixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 3-ethynylbenzylcarbamate (247 mg), trans- dichlorobis(triphenylphosphine)palladium(π) (31.3 mg) and coppeπT) iodide (10.2 mg) were sequentially added. The title compound (376 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.24 (3H, s), 2.53 (3H, s), 4.00 (2H, br s), 4.32 (2H, d, J= 6 Hz),

5.04 (IH, br s), 6.87 (IH, d, J= 9 Hz), 7.01 (IH, br s), 7.09-7.5 (9H, m), 8.22 (IH, d, J= 2 Hz), 8.34 (IH, s).

(ii) Production of tert-butyl 3-[4-({3-me1hyl-4-[(6-memylpyridm-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrirnidin-6-yl]benzylcarbamate

The title compound (287 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using tert-butyl 3-{[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammό)pyrimidin-4-yl]ethynyl}benzylcarbamate (363 mg) and copperQ iodide

(12.9 mg).

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 2.17 (3H, s), 2.51 (3H, s), 4.23 (2H, br s), 5.67 (IH, br s), 6.72

(IH, s), 6.82 (IH, d, J= 8 Hz), 6.9-7.7 (8H, m), 8.16 (IH, br s), 8.60 (IH, s), 8.66 (IH₅ br s), 10.64

(lH, br s). (iϋ) Production of 6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-

5H-pynOlo[3,2-d]pyrrmidin-4-amine tert-Butyl 3-[4-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrrmidin-6-yl]benzylcarbamate (230 mg) was suspended in tetrahydrofuran (2.3 mL), 2N hydrochloric acid (2.3 mL) was added, and the mixture was stirred with heating at 60°C for 3 hrs. After cooling to room temperature, IN aqueous sodium hydroxide solution (4.6 mL) was added, and the mixture was stirred at room temperature for 5 min. The solvent was removed by decantation, and the residue was dissolved in tetrahydrofuran (30 mL), dried over potassium carbonate, and concentrated under reduced pressure. The residue was triturated with dϋsopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (164 mg). ¹H-NMR (DMSO-de) δ: 2.18 (3H, s), 2.41 (3H, s), 3.92 (2H, br s), 4.86 (2H, br s), 6.9-8.2 (1 IH, m), 8.33 (IH, s), 9.62 (IH, br s), 12.13 (IH, br s). Synthesis Example 15

Production of 2-methoxy-N-{3-[4-({3-methyl-4-[(6-methylpyriαm-3-yl)oxy]phenyl}amino)-5H- pyrrolo [3 ,2-d]pyrimidin-6-yl]benzyl} acetamide

The title compound (56 mg) was obtained by the reaction in the same manner as in

Synthesis Example 11 using 6-[3-(aminomethyl)phenyl]-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrirmdin-4-amine (50 mg), methoxyacetic acid (0.01055 mL),

1-hydroxybenzotriazolemonohydrate (23.2 mg), N,N-dimethylformamide (2.3 ml), l-ethyl-3-(3- dimemylaminopropyl)carbodiimide hydrochloride (32.9 mg) andtriethylamine (0.080 mL).

¹H-NMR (DMSO-d_δ) δ: 2.27 (3H, s), 2.52 (3H, s), 3.44 (3H, s), 3.98 (2H, s), 4.56 (2H, d, J= 6 Hz),

6.65 (IH, s), 6.82 (IH, d, J= 2 Hz), 6.93 (IH, d, J= 8 Hz), 7.11 (2H, m), 7.3-7.9 (6H, m), 8.22 (IH, m), 8.47 (IH, s), 8.82 (IH, br s), 11.26 (IH, br s).

Synthesis Example 16

05

Production of 6-(aminome1hyl)-N-{3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine

(i) Production of tert-butyl 3-[5-arnino-6-({3-methyl-4-[(6-meth.ylpyridin-3- yl)oxy]phenyl}amino)pyiitiύdin-4-yl]-2-propynylcarbamate 5 6-Iodo-N4-{3-me1hyl-4-[(6-me1hylpyridm hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 2-propynylcarbamate (166 mg), trans- dicUorobis(1riphenylphosphine)palladium(ir) (31.3 mg) and copper(T) iodide (10.2 mg) were sequentially added. The title compound (303 mg) was obtained as a powder by the reaction in the i o same manner as in Synthesis Example 9 (iv).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.22 (3H, s), 2.52 (3H, s), 4.06 (2H₅ br s), 4.17 (2H, d, J= 6 Hz),

5.09 (IH, br s), 6.84 (IH, d, J= 9 Hz), 7.0 - 7.5 (4H, m), 8.20 (IH, d, J= 3 Hz), 8.25 (IH, s).

(ϋ) Production of tert-butyl [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo [3 ,2-d]pyrimidin-6-yl]methylcarbamate 5 The title compound (212 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using tert-butyl 3-[5-amino-6-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}arnino)pyrirnidin-4-yl] -2-propynylcarbamate (286 mg) and copper(T) iodide (11.8 mg).

¹H-NMR (CDCl₃) δ: 1.38 (9H, s)₅2.20 (3H, s), 2.52 (3H, s), 4.30 (2H, d, J= 6 Hz)₅ 5.38 (IH, t, J= 60 Hz), 6.32 (IH₅ br s), 6.83 (IH, d, J= 9 Hz)₅7.07 (IH₅ d, J= 9 Hz)₅7.1-7.4 (4H₅ m), 7.84 (IH₅ br s)₅

8.20 (IH₅ d₅ J= 2 Hz)₅ 8.50 (IH₅ s), 9.95 (IH₅ br s).

(iϋ) Production of 6-(arninome1hyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3 ,2-d]pyrimidin-4-amine The title compound (160 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 14 (ϋi) using tert-butyl [4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}arrύno)-5H-pyrrolo[3,2-d]pyrimidin-6-yl]methylcarbamate (165 mg), 2N hydrochloric acid (1.92 mL) and tetrahydrofuran (1.92 mL).

5 ¹H-NMR (DMSOd₆) δ: 2.17 (3H, s), 2.42 (3H, s), 3.59 (2H, t, J= 6 Hz)₅3.95 (2H, s), 6.25 (IH, s), 6.86 (IH, s), 6.94 (IH, d, J= 8 Hz), 7.1-7.3 (2H, m), 7.78 (2H, m), 8.14 (IH₃ d, J= 3 Hz), 8.26 (IH, s), 9.46 (IH, br s), 11.50 (IH, br s). Synthesis Example 17

i o Production of (2E)-4-(dime1hylamino)-N-{[4-({3-memyl4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrirrύdin-6-yl]methyl}-2-butenamide

The title compound (32 mg) was obtained by the reaction in the same manner as in Synthesis Example 11 using 6-(ammomethyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin-4-amine (40 mg), (2E)-4-(dimethylamino)-2-butenoic acid

15 hydrochloride (22 mg), 1 -hydroxybenzotriazole monohydrate (22.5 mg), N,N-dimemylformamide (2.2 mL), l-emyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31.9 mg) and triethylamine (0.0928 mL).

¹H-NMR (DMSOd₆) δ: 2.15 (6H, s), 2.19 (3H, s), 2.43 (3H, s), 3.01 (2H, d, J= 5 Hz), 4.55 (2H, d, J= 5 Hz), 6.12 (IH, d, J= 16 Hz), 6.36 (IH, d, J= 1 Hz), 6.68 (IH, m), 6.96 (IH, d, J= 8 Hz), 7.18 0 (2H, m), 7.74 (2H, m), 8.16 (IH, d, J= 3 Hz), 8.30 (IH, s), 8.70 (IH, t, J= 5 Hz), 9.30 (IH, br s), 11.03 (IH, br s).

Synthesis Example 18

Production of 6-[(lE)-3-atrmo-l-propen-l-yl]-N-{3-me1hyl-4-^^ 5 5H-pyrrolo[3,2-d]pyrimidin-4-arnine

(i) Production of tert-butyl (2E)-5-[5-amino-6-({3-mefhyl-4-[(6-rnethylpyridin-3- yl)oxy]phenyl}arnino)pyrirnidin-4-yl]-2-penten-4-yn-l-ylcarbamate 6-Iodo-N4-{3-methyl-4-[(6-methylpyridM hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 o mL), and tert-butyl (2E)-2-penten-4-yn- 1 -ylcarbamate (194 mg), trans- dicUorobis(1riphenylphospbJne)palladium(ir) (31.3 mg) and copperQ iodide (10.2 mg) were sequentially added. The title compound (199 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (iv).

¹H-NMR (CDCl₃) δ: 1.46 (9H₅ s), 2.20 (3H, s), 2.52 (3H, s), 3.85 (2H, m), 4.22 (2H, br s), 5.02 (IH, br s), 5.84 (IH, d, J- 16 Hz), 6.29 (IH, m), 6.84 (IH, d, J= 9 Hz), 7.0-7.5 (5H, m), 8.19 (IH, d₅ J= 2

Hz), 8.26 (IH, s).

(ϋ) Production of tert-butyl (2E)-3-[4-({3-methyl-4-[(6-methylpyridrn-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3₅2-d]pyrimidin-6-yl]-2-propenylcarbamate

The title compound (66 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using tert-butyl (2E)-5-[5-amino-6-({3-methyl-4-[(6-methylpyridin- 3-yl)oxy]phenyl}amino)pyriinidm-4-yl]-2-penten-4-yn-l-ylcarbamate (195 mg) and copper(T) iodide (7.63 mg).

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 2.12 (3H₃ s), 2.49 (3H, s), 3.82 (2H, br s), 5.53 (IH, br s), 6.00

(IH, d, J= 16 Hz)₅ 6.36 (IH₅ m), 6.77 (IH, d, J= 9 Hz), 7.0-7.5 (4H₅ m), 8.09 (IH, s), 8.43 (IH₅ br s), 5 8.51 (IH, br s)₅ 11.00 (IH₅ br s).

(iii) Production of 6-[(lE)-3-amino-l-proρen-l-yl]-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-arnine

The title compound (41 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 14 (iii) using tert-butyl (2E)-3-[4-({3-methyl-4-[(6-methylpyridin-3- i o yl)oxy]phenyl}amino)-5H-pynrolo[3₅2-d]pyrimidin-6-yl]-2-propenylcarbamate (65 mg), 2N hydrochloric acid (0.755 mL) andtetrahydroruran (0.755 mL).

¹H-NMR (DMSOd₆) δ: 2.17 (3H₅ s), 2.42 (3H₅ s), 3.41 (2H, m), 6.40 (IH₅ s), 6.62 (2H₅ m), 6.96

(IH₅ d, J= 8 Hz)₅ 7.17 (2H₅ m), 7.95 (2H, m), 8.16 (IH, d, J= 3 Hz)₅ 8.28 (IH, s), 10.09 (IH₅ br s),

12.43 (IH₅ br s). 15 Synthesis Example 19

Production of 2-methoxy-N- { (2E)-3 -[4-({ 3 -methyl-4-[(6-methylpyridin-3 -yl)oxy]phenyl} arnino)- 5H-pyrrolo[3₅2-d]pyrimidin-6-yl] -2-propenyl} acetamide

The title compound (15 mg) was obtained by the reaction in the same manner as in 0 Synthesis Example 11 using 6-[(lE)-3-aminopropen-l-yl]-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (50 mg), methoxyacetic acid (0.0119 mL), 1- hydroxybenzotriazolemonohydrate (26.2 mg), N,N-dimethylformamide (2.56 mL), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (37.2 mg) andtriethylamine (0.090 mL). 1H-NMR (DMSOd₆) δ: 2.20 (3H, s), 2.43 (3H, s), 3.36 (3H, s), 3.88 (2H, s), 3.97 (2H, t, J= 5 Hz), 5 6.32 (IH, m), 6.49 (IH, d, J= 1 Hz), 6.56 (IH, d, J= 17 Hz), 6.97 (IH, d, J= 9 Hz), 7.19 (2H, m), 7.75 (2H, m), 8.15 (IH, d, J= 2 Hz), 8.24 (IH, t, J= 5 Hz), 8.29 (IH, s), 9.04 (IH, br s), 11.33 (IH, br s). Synthesis Example 20

i o Production of (2E)-3-[5-ethyl-4-({3-me1hyl-4-[(6-me1hylpyridm-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-l-ol

(i) Production of 4-iodo-6-phenoxypyrimiαln-5-arnine

4,6-Diiodopyrimidin-5-amine (2.2 g) was dissolved in l-methyl-2-pyrrolidone (11.5 mL), phenol (656 mg) and potassium carbonate (964 mg) were added, and the mixture was stirred at 15 100°C for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate

(200 mL) and washed successively with water (100 mL) and saturated brine (100 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 ->

20:80) to give the title compound (2.0 g) as an oil. 0 ¹H-NMR (CDCl₃) δ: 4.34 (2H, br s), 7.1-7.5 (5H, m), 7.87 (IH, s). (ii) Production of 4-((3E)-5- { [tert-butyl(dimethyl)silyl]oxy} -3-penten- 1 -ynyl)-6-phenoxypvrimidin-

5-amine

4-Iodo-6-phenoxypvrirrήdrn-5-amine (1.0 g) was dissolved in a mixed solvent of acetonitrile (53 rnL)/triethylamine (39 mL), andtert-butyl(dimethyl)[(2E)-2-penten-4- ynyloxyjsilane (753 mg), tøm-dicUorobis(Mphenylphosphine)palladium(II) (112 mg) and copperQ iodide (36.5 mg) were sequentially added. The title compound (1.07 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (iv).

¹H-NMR (CDCl₃) δ: 0.09 (6H, s), 0.93 (9H, s), 4.32 (2H₅ m), 4.42 (2H₃ br s), 6.08 (IH, dt, J= 16 Hz,

3 Hz), 6.48 (IH, dt, J= 16 Hz₅4 Hz)₅7.1-7.5 (5H, m), 8.11 (IH, s). (iii) Production of 6-((lE)-3-{[tert-butyl(dimethyl)silyl]oxy}-l-propenyl)-4-phenoxy-5H- pyrrolo[3₅2-d]pyrimidine

The title compound (409 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 9 (v) using 4-((3E)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-penten-l-ynyl)-6- phenoxypyrimidin-5-amine (950 mg) and copper(T) iodide (47.4 mg). 1H-NMR (CDCl₃) δ: 0.12 (6H₅ s), 0.95 (9H₅ s)₅4.39 (2H₅ m), 6.44 (IH, dt, J= 16 Hz₅4 Hz), 6.67

(2H₅ m), 7.1-7.5 (5H₅ m), 8.48 (IH, s), 9.07 (IH₅ br s).

(iv) Production of 6-((lE)-3 - { [tert-butyl(dimethyl)silyl]oxy} - 1 -propenyl)-5-ethyl-4-phenoxy-5H- pyrrolo[3,2-d]pyrimidine

6-((lE)-3-{[tert-Butyl(dimethyl)silyl]oxy}-l-propenyl)-4-phenoxy-5H-pyrrolo[3,2- djpyrimidine (100 mg) was dissolved in N,N-dmethylformamide (0.786 mL), cesium carbonate

(102.6 mg) was added, and the mixture was stirred at room temperature for 20 min. Iodoethane

(0.0231 mL) was added and the mixture was stirred at room temperature for 2 hrs and at 40⁰C for 4 hrs. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL) and washed successively with water (30 mL) and saturated brine (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 50:50) to give the title compound (79 mg) as an oil. 1H-NMR (CDCl₃) δ: 0.14 (6H, s), 0.97 (9H, s), 1.44 (3H, t, J= 7 Hz), 4.44 (2H, m), 4.52 (2H, q, J= 7 Hz), 6.58 (IH, dt, J- 15 Hz, 4 Hz), 6.74 (IH, s), 6.78 (IH, m), 7.2-7.5 (5H, m), 8.41 (IH, s). (v) Production of (2E)-3-[5-ethyl-4-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyiτolo[3,2-d]pyrirnidin-6-yl]-2-propen-l-ol

Arriixlure of6-((lE)-3-{[tert-butyl(dime1hyl)silyl]oxy}-l-propenyl)-5-ethyl-4-phenoxy- 5H-pyrrolo[3,2-d]pyrimidine (78 mg), 3-me1hyl-4-[(6-memylpyridin-3-yl)oxy]anUine (61.2 mg), pyridine hydrochloride (26 mg) and phenol (122 mg) was stirred with heating at 120⁰C for 16 hrs. After cooling to room temperature, the mixture was diluted with dichloromethane (30 mL), and washed with saturated aqueous sodium hydrogen carbonate (20 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > 80:20) to give the title compound (32 mg) as a powder.

¹H-NMR (CDCl₃) δ: 1.46 (3H, t, J= 7 Hz), 2.24 (3H, s), 2.53 (3H₅ s), 4.31 (2H, q, J= 7 Hz), 4.42 (IH, dd, J= 5 Hz, 2 Hz), 6.54 (IH, dt, J= 15 Hz, 5 Hz), 6.66 (IH, s), 6.70 (IH, d, J= 15 Hz), 6.88 (IH, d, J= 8 Hz), 7.0-7.4 (4H, m), 8.20 (IH, d, J= 2 Hz), 8.46 (IH, s). Synthesis Example 21

Production of [4-({3-cMoro-4-[(3-fluoroben2yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrirnidin-6^ yljmethanol hydrochloride

(i) Production of 3-(5-amino-6-phenoxypyrirnidin-4--yl)-2-propyn-l-ol 4-Iodo-6-phenoxypyrimidin-5-arnine (3.0 g) was dissolved in a mixed solvent of acetonitrile (159 mL)/triethylarnine (117 mL), and 2-propyn-l-ol (0.669 mL), trans- dichlorobis(triphenylphosphine)palladium(ir) (336 mg) and copper(T) iodide (109.5 mg) were sequentially added. The title compound (2.02 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (iv). 1H-NMR (CDCl₃) δ: 3.53 (IH, br s), 4.52 (2H, br s), 4.63 (2H, br s), 7.1-7.5 (5H, m), 8.09 (IH, s).

(ϋ) Production of (4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)methanol

The title compound (1.31 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (v) using 3-(5-arnino-6-phenoxypyrimidin-4-yl)-2-propyn-l-ol (1.98 g) and copper(T) iodide (156 mg). 1H-NMR (DMSO-dβ) δ: 4.67 (2H, d, J= 5 Hz), 5.45 (IH, t, J= 5 Hz), 6.50 (IH, s), 7.2-7.5 (5H, m),

8.26 (IH, s), 12.15 (IH, br s).

(iϋ) Production of [4-({3-cUoro4-[(3-fiuorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirnidin-6-yl]methanol hydrochloride

The title compound (142 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 1 using (4-phenoxy-5H-pyrrolo[3,2-d]pyrinτidin-6-yl)methanol (100 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (156 mg), pyridine hydrochloride (56.7 mg) and 1-methyl- 2-pyrrolidone (0.828 mL).

¹H-NMR (DMSOd₆) δ: 4.76 (2H, s), 5.27 (2H, s), 6.50 (IH, d, J= 2 Hz), 7.1-7.6 (5H, m), 7.73 (IH, 5 dd, J= 3 Hz, 9 Hz), 8.12 (IH, d, J= 3 Hz), 8.77 (IH, s), 11.50 (IH, br s). Synthesis Example 22

Production of (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl} amino)-5-methyl-5H- pyrrolo[3,2-d]pyrimidin-6-yl]-2-propen-l-ol i o (i) Production of (2E)-5-(5-amino-6-phenoxypyrimidin-4-yl)-2-penten-4-yn-l-ol

4-Iodo-6-phenoxvpyrimidin-5-amine (3.5 g) was dissolved in a mixed solvent of acetonitrile (185 mL)/triethylamine (136 mL), and 2-penten-4-yn-l-ol (1.1 g), trans- dcMorobis(triphenylphosphine)palladium(π) (392 mg) and copper(T) iodide (127 mg) were sequentially added. The title compound (1.79 g) was obtained as a powder by the reaction in the 15 same manner as in Synthesis Example 9 (iv).

¹H-NMR (CDCl₃) δ: 2.48 (IH, br s), 4.33 (2H, dd, J= 5 Hz, 2 Hz), 4.45 (2H, br s), 6.12 (IH, dt, J= 2

Hz, 16 Hz), 6.54 (IH, dt, J= 16 Hz, 5 Hz), 7.1-7.5 (5H, m), 8.11 (IH, s).

(ii) Production of (2E)-3 ~(4-phenoxy-5H-pyrrolo[3 ,2-d]pyrimidin-6-yl)-2-propen- 1 -ol

The title compound (1.25 g) was obtained as crystals by the reaction in the same manner as in Synthesis Example 9 (v) using (2E)-5-(5-anmo-6-phenoxypyrimidin-4-yl)-2-penten-4-yn-l-ol

(1.7 g) and copper(T) iodide (268 mg).

¹H-NMR (CDCl₃) δ: 2.38 (IH, br s), 4.41 (2H, d, J= 4 Hz), 6.58 (IH, dt, J= 3 Hz, 16 Hz), 6.66 (IH, s), 6.75 (IH, d, J= 16 Hz), 7.2-7.5 (5H, m), 8.48 (IH, s), 9.73 (IH, br s). 5 (iϋ) Production of (2E)-3-(4-phenoxy-5H-pyrrolo[3,2-d]pyrirnidin-6-yl)-2-propenyl benzoate

(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrirnidin-6-yl)-2-propen-l-ol (1.0 g) was suspended in tetrahydrofuran (20 mL), and triethylamine (0.651 mL) and benzoyl chloride (0.86 mL) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, diluted with ethyl acetate (200 mL) and washed with water (50 mL). The organic layer was dried over i o magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -» 0:100) to give the title compound (1.08 g) as crystals.

¹H-NMR (CDCl₃) δ: 5.03 (2H, d, J= 6 Hz), 6.52 (IH, m), 6.72 (IH, dt, J= 16 Hz, 2 Hz), 6.80 (IH, d,

J= 16 Hz), 7.1-7.7 (8H, m), 8.08 (2H, m), 8.50 (IH, s), 9.27 (IH, br s). is (W) Production of (2E)-3-(5-me1hyl-4-phenoxy-5H-pyrτolo[3,2-d]pyrirnidin-6-yl)-2-propenyl benzoate

(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate (500 mg) was dissolved in N,N-dimethylformamide (4 mL), and potassium carbonate (279 mg) and iodomethane

(0.1 mL) were sequentially added. After stirring at room temperature for 4 hrs, water (30 mL) was 0 added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 — > 50:50) to give the title compound (301 mg) as crystals. ¹H-NMR (CDCl₃) δ: 4.14 (3H, s), 5.08 (2H, dd, J= 6 Hz, 1 Hz)₃ 6.66 (IH, m), 6.84 (IH, s), 6.85 (IH, d, J= 16 Hz), 7.2-7.7 (8H, m), 8.10 (2H, d, J= 9 Hz), 8.42 (IH, s). (v) Production of (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}araiαo)-5-methyl-5H- pyrrolo [3 ,2-d]pyrimidin-6-yl]-2-propen- 1 -ol

5 A mixture of (2E)-3-(5-me1iiyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propenyl benzoate (100 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (130 mg), pyridine hydrochloride (36 mg) and l-methyl-2-pyrrolidone (0.518 mL) was stirred with heating at 140⁰C for 4 hrs. After cooling to room temperature, aqueous sodium hydrogen carbonate (20 mL) was added to the reaction mixture and the mixture was extracted with ethyl acetate (100 mL). The organic layer was i o dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.518 mL)/ethanol (0.518 mL), IN aqueous sodium hydroxide solution (0.518 mL) was added, and the mixture was stirred at room temperature for 2 hrs. Tetrahydrofuran/ethyl acetate (1:1, 50 mL) and saturated brine (30 mL) were added, and the mixture was extracted. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The is residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — >^■ 85:15) to give the title compound (45 mg) as crystals. 1H-NMR (DMSOd₆) δ: 4.00 (3H, s), 4.21 (2H, t, J= 4 Hz), 5.07 (IH, t, J= 5 Hz), 5.23 (2H, s), 6.58 (IH, m), 6.68 (IH, s), 6.80 (IH, d, J= 16 Hz), 7.1-7.8 (7H, m), 8.21 (IH, s), 8.49 (IH, br s). Synthesis Example 23

Production of (2E)-3-[5-methyl-4-({3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}ainino)-5H- pyrrolo[3,2-d]pyrirnidin-6-yl]-2-propen-l-ol

The title compound (60 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 22 (v) using (2E)-3-(5-me1hyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidrn-6-yl)- 5 2-propenyl benzoate (100 mg), 3-methyl-4-[(6-methylpyriάlα-3-yl)oxy]aniline (111 mg), pyridine hydrochloride (36 mg) and l-methyl-2-pyrrolidone (0.518 mL).

¹H-NMR (DMSOd₆) δ: 2.16 (3H, s), 2.43 (3H, s), 4.02 (3H, s), 4.22 (2H, br s), 5.07 (IH, t, J= 5 Hz), 6.60 (IH, m), 6.69 (IH, s), 6.80 (IH, d, J= 16 Hz), 6.93 (IH, d, J= 9 Hz), 7.1-7.6 (5H, m), 8.16 (IH, d, J= 2 Hz), 8.23 (IH, s), 8.54 (IH, br s). i o Synthesis Example 24

Production of N- {3-chloro-4-[(3-fluorobenzyl)oxy]phenyl} -5-[(3 ,4-dimethoxyphenyl)sulfonyl]-5H- pyrrolo[3,2-d]pyrimidin-4-amine

N- {3 -Chloro-4-[(3 -fluorobenzyl)oxy]phenyl} -5H-pyrrolo [3 ,2-d]pyrirnidin-4-amine 5 hydrochloride (150 mg) was dissolved in N,N-dimethylformamide (1.5 mL), and potassium carbonate (102 mg) and (3,4-dimethoxyphenyl)sulfonyl chloride (96.9 mg) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, and at room temperature for 1 hr. The mixture was diluted with ethyl acetate (50 mL) and washed twice with water (30 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 0:100) to give the title compound (95 mg) as a powder.

¹H-NMR (CDCl₃) δ: 3.68 (3H, s), 3.86 (3H₅ s), 5.16 (2H, s), 6.76 (IH, d, J= 4 Hz), 6.82 (IH, d, J= 9 Hz), 6.97 (IH, d, J= 9 Hz), 7.02 (IH, m), 7.1-7.4 (5H, m), 7.55 (IH, dd, J= 9 Hz, 3 Hz), 7.79 (IH, d, J= 4 Hz), 7.94 (IH, d, J= 3 Hz), 8.52 (IH, s), 9.39 (IH, br s). Synthesis Example 25

Production of ethyl 5-{[4-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]methyl}-2-fbroate (i) Production of ethyl 5-[(4-cMoro-5H-pyrrolo[3,2-d]pyrrmidin-5-yl)methyl]-2-furoate

To a suspension of 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) inN,N- dimethylformamide (6.5 mL) was added potassium carbonate (541 mg) under ice-cooling, and the mixture was stirred for 15 min. while warming to room temperature. Ethyl 5-(chloromethyl)-2- furoate (737 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL), and extracted with a mixed solvent (40 mLx3) of ethyl acetate/tetrahydrofuran (1/1) . The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=80/20 -» 10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (825 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 1.37 (3H, t, J= 7.2 Hz), 4.36 (2H, q, J= 7.2 Hz), 5.75 (2H, s), 6.30 (IH, ddd, J= 0.9, 2.1, 2.7 Hz), 6.80 (IH, t, J= 3.9 Hz), 7.10 (IH, t, J= 3.3 Hz), 7.63 (IH, dd, J= 2.7, 3.3 Hz), 8.73 5 (IH, d, J= 3.9 Hz).

(ii) Production of ethyl 5-{[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl} -2-furoate

To a solution of ethyl 5-[(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (200 mg) in l-methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (247 i o mg), and the mixture was heated to 140°C and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (20 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluentethyl

15 acetate/methanol=10/0 ->^• 8/2). The object fraction was concentrated under reduced pressure and dried to give the title compound (307 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 1.34 (3H, t, J= 7.2 Hz), 4.38 (2H, q, J= 7.2 Hz), 5.14 (2H, s), 5.49 (2H, s), 6.45 (IH, d, J= 3.4 Hz), 6.63 (IH, d, J= 3.0 Hz), 6.94 (IH, d, J= 8.8 Hz), 7.03 (IH, d, J= 9.6 Hz), 7.26- 7.38 (6H, m), 7.43 (IH, dd, J= 2.6, 8.8 Hz), 7.65 (IH, d, J= 3.0 Hz), 8.50 (IH, s). 0 Synthesis Example 26

Production of 5-{[4-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyiimidin-5-yl]methyl} -2-furancarboxylic acid

To a solution of ethyl 5-{[4-({3-cMoro-4-[(3-fluoroberizyl)oxy]phenyl}arnino)-5H- 5 pyrrolo [3 ,2-d]pyrirrddin-5-yl]methyl} -2-furoate (280 mg) in a mixed solvent of tetrahydrofuran (1.34 mL) and ethanol (1.34 mL) was added IN aqueous sodium hydroxide solution (1.34 mL) and the mixture was stirred at room temperature for 14 hrs. IN Hydrochloric acid (1.34 mL) and water (10 mL) were added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mLx3) and i o dϋsopropyl ether (10 mLx3) and dried under reduced pressure (80⁰C) to give the title compound (178 mg) as a white powder.

¹H-NMR (DMSOd₆) δ 5.24 (2H, s), 5.89 (2H, s), 6.37 (IH, d, J= 3.3 Hz), 6.54 (IH, d, J= 2.7 Hz), 7.10 (IH, d, J= 3.3 Hz), 7.21 (2H, d, J= 9.0 Hz), 7.32 (2H, t, J= 6.6 Hz), 7.48 (2H, 1, J= 8.1 Hz), 7.73 (2H, d, J= 9.6 Hz), 8.29 (IH, s), 8.57 (IH, br s).

15 Synthesis Example 27

Production of N-{3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}-5-{4-[(cis-3,5-dimethylpiperaziii-l- yl)carbonyl]benzyl}-5H-pyrrolo[3,2-d]pyrirnidin4-amine

To a solution of 4-{[4-({3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- 5 d]pyrimidin-5-yl]methyl}benzoic acid (120 mg) in N,N-dimethylformamide (2.4 mL) were added cis-2,6-dimethylpiperazine (95 mg) and lH-l,2,3-benzotriazol-l-ol (65 mg), and the mixture was stirred at room temperature for 15 min. N-[3-(Dimethylarnino)propyl]-N'-emylcarbodiimide hydrochloride (92 mg) and Methylamine (0.2 mL) were added, and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water (20 mL) and extracted with i o ethyl acetate (25 mLx3). The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -> 9/1). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (3/7) was added to the residue and the resultant precipitate was

15 collected by filtration and dried under reduced pressure to give the title compound (85 mg) as white powder crystals.

¹H-NMR(CDCl₃) δ 1.13 (6H, d, J= 6.6 Hz), 1.66 (4H, br s), 2.69 (2H, br), 3.41 (IH, brd, J= 6.6 Hz), 4.60 (IH, brd, J= 13.5 Hz), 5.08 (2H, s), 5.56 (2H₃ s), 6.28 (IH, s), 6.68 (IH, dd, J= 2.1, 5.4 Hz), 6.82 (IH, d, J= 9.3 Hz), 7.00 (2H, dt, J= 2.1, 8.7 Hz), 7.15-7.21 (4H, m), 7.25 (IH, d, J= 2.4 Hz), 7.30-7.38 (4H, m), 7.48 (2H, d, J= 8.4 Hz), 8.48 (IH, s). Synthesis Example 28

Production of N-[3-cHoro-4-(pyridin-2-ylme1hoxy)phenyl]-5H^^ To a solution of 4-cUoro-5H-pyrrolo[3,2-d]pyrirnidine (63 mg) in l-methyl-2-pyrrolidone

(0.8 mL), was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (149 mg), and the mixture was heated to 140°C and stirred for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with a mixed solvent (25 mLx3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -> 8/2). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (112 mg) as pale-yellow powder crystals.

¹H-NMR (DMSOd₆) δ 5.27 (2H, s), 6.48 (IH, d, J= 2.4 Hz), 7.25 (IH, d, J= 8.7 Hz)₅7.37 (IH, dd, J= 5.1, 7.5 Hz), 7.55-7.60 (2H, m), 7.66 (IH, s), 7.89 (IH, t, J= 7.5 Hz), 8.20 (IH, dd, J= 1.5, 2.4 Hz), 8.35 (IH, d, J= 1.5 Hz), 8.60 (IH, dd, J= 0.6, 4.8 Hz), 9.25 (IH, s), 12.78 (IH, s). Synthesis Example 29

Production of ethyl 5-[(4-{[3-cUoro-4-(pyridin-2-ylme1hoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrinddin-5-yl)methyl]-2-furoate

To a solution of ethyl 5-[(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]-2-furoate (300 5 mg) in l-methyl-2-pyrrolidone (2.0 mL) was added 3-cMoro-4-(pyridin-2-ylmethoxy)aniliαe (360 mg), and the mixture was heated to 140°C and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (30 mL) and extracted with a mixed solvent (45 mLx3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent i o was evaporated under reduced pressure, and the obtained residue was subj ected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -> 8/2). The object fraction was concentrated under reduced pressure. Chloroform/dϋsopropyl ether (1/9) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (440 mg) as pale-yellow powder crystals. is ¹H-NMR (CDCl₃) δ 1.37 (3H, t, J= 7.2 Hz), 4.36 (2H, q, J= 7.2 Hz), 5.33 (2H, s), 5.91 (2H, s), 6.39 (IH, d, J= 3.4 Hz), 6.57 (IH, d, J= 2.6 Hz), 7.12 (IH, d, J= 3.4 Hz), 7.23 (IH, d, J= 9.0 Hz), 7.43 (IH, dd, J= 4.8, 7.8 Hz), 7.50 (IH, dd, J= 2.2, 9.2 Hz)₅7.61 (IH, d, J= 7.8 Hz), 7.75 (2H, s), 7.90 (IH, dt, J= 1.2, 7.8 Hz), 8.14 (IH, d, J= 4.8 Hz), 8.30 (IH, s), 8.55 (IH, br s). Synthesis Example 30

Production of 5-[(4-{[3-cUoro-4-(pyridin-2-ylme1hoxy)phenyl]ammo}-5H-pyrrolo[3,2- flpyrimidin-S-y^niethylJ^-furancarboxylic acid

To a solution of ethyl 5-[(4-{[3-cMoro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyriirddin-5-yl)methyl]-2-furoate (440 mg) in a mixed solvent of tetrahydrofuran (2.0 mL) and ethanol (2.0 mL) was added IN aqueous sodium hydroxide solution (2.0 mL), and the mixture was stirred at room temperature for 5 hrs. IN Hydrochloric acid (2.0 mL) and water (25 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mLx3) and dϋsopropyl ether (10 mLx3), and dried under reduced pressure (80⁰C) to give the title compound (310 mg) as white powder crystals.

¹H-NMR (DMSOd₆) δ 5.27 (2H, s), 5.88 (2H, s), 6.35 (IH, d, J= 3.4 Hz), 6.53 (IH, d, J= 2.6 Hz), 7.08 (IH, d, J= 3.4 Hz), 7.20 (IH, d, J- 9.0 Hz), 7.37 (IH, dd, J= 4.8,7.8 Hz), 7.47 (IH, dd₅ J= 2.2, 9.2 Hz), 7.58 (IH, d, J= 7.8 Hz), 7.73 (2H, s), 7.88 (IH, t, J= 1.2, 7.8 Hz), 8.27 (IH, s), 8.53 (IH, br s), 8.59 (IH, d, J= 4.8 Hz). Synthesis Example 31

Production of ethyl 2-(3,5-dcUorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate To a solution of 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (61 mg) in l-methyl-2-pyrrolidone (0.8 mL), was added ethyl 5-amino-2-(3,5-dichlorophenoxy)benzoate (186 mg), and the mixture 5 was heated to 140⁰C and stirred for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (25 mLx3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column i o chromatography (basic silica gel, eluenthexane/ethyl acetate=8/2 — » 0/10). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (149 mg) as pale-yellow powder crystals. 1H-NMR (DMSOd₆) δ 1.10 (3H, t, J= 7.2 Hz), 4.18 (2H, q, J= 7.2 Hz), 6.52 (IH, d, J= 2.8 Hz),

25 6.90 (2H, t, J= 3.0 Hz), 7.28 (IH, dd, J= 1.8, 2.8 Hz), 7.33 (IH, dd, J= 8.8 Hz), 7.71 (IH, d, J= 2.8 Hz), 8.36 (2H, d, J= 8.8 Hz), 8.39 (IH, d, J- 1.8 Hz), 9.60 (IH, s), 11.15 (IH, s). Synthesis Example 32

Production of 2-(3,5~dicMorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrin^

To a solution of ethyl 2-(3,5-dicUorophenoxy)-5-(5H-pyrrolo[3,2-d]pyrimidin-4- ylamino)benzoate (100 mg) in a mixed solvent of tetrahydrofuran (0.68 mL) and ethanol (0.68 niL) 5 was added IN aqueous sodium hydroxide solution (0.68 mL), and the mixture was stirred at room temperature for 16 hrs. IN Hydrochloric acid (0.68 mL) and water (5 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The resultant precipitate was collected by filtration, washed with water (10 mL><3) and diisopropyl ether(10 mLx3) and dried under reduced pressure (80°C) to give the title compound (76 mg) as white i o powder crystals.

¹H-NMR (DMSO-d_δ) δ 6.52 (IH, d, J= 1.2 Hz), 6.90 (2H, t, J= 12 Hz)₅7.28 (2H, dt, J= 3.0, 5.1 Hz)₅7.71 (IH, t, J= 2.7 Hz)₅ 8.29 (IH₅ dd, J= 2.7, 8.7 Hz)₅ 8.37 (IH, d, J= 2.7 Hz)₅ 8.40 (IH₅ d₅ J= 1.2 Hz)₅ 9.59 (IH, s), 11.18 (IH, br s). Synthesis Example 33

Production of N- {3 -chloro-4- [(3 -fluorobenzyl)oxy]phenyl} -5-ethyl-5H-pyrrolo [3 ,2-d]pyrimidin-4- amine

(i) Production of 4-cMoro~5-emyl-5H~pyrrolo[3,2-d]pyrimidine

To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrirnidine (200 mg) in N₅N- 5 dimethylformamide (1.3 mL) was added potassium carbonate (269 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodoethane (305 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium o sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subj ected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=80/20 -» 10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (187 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 1.52 (3H₅ t, J= 7.2 Hz), 4.55 (2H, q, J= 7.2 Hz)₅ 6.73 (IH, d, J= 3.2 Hz)₅7.51s (IH₅ d, J= 3.2 Hz)₅ 8.70 (IH, s).

(ϋ) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-ethyl-5H-pyrrolo[3 ,2- d]pyrimidin-4-amine

To a solution of 4-cWoro-5-ethyl-5H-pyrrolo[3,2-d]pyrimidine (85 mg) in l-methyl-2- pyrrolidone (0.94 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (177 mg). The title o compound (98 mg) was obtained as a pale-purple powder crystals by the reaction in the same manner as in Synthesis Example 29.

¹H-NMR (CDCl₃) δ 1.56 (3H₅ T₅ J= 7.4 Hz)₅4.33 (2H, q, J= 7.4 Hz)₅ 5.15 (2H, s), 6.51 (IH₅ br s),

6.58 (IH, d₅ J= 3.0 Hz)₅ 6.72 (2H, s), 6.95 (IH, d, J= 8.7 Hz)₅7.02 (IH₅ m), 7.21 (IH₅ d, J= 8.5 Hz)₅ 7.25 (IH, d, J= 3.0 Hz), 7.33-7.40 (2H, m), 7.60 (IH, d, J= 2.5 Hz), 8.49 (IH, br s). Synthesis Example 34

Production of 5-efhyl-N- {3 -mefhyl-4-[(6-methylpyridin-3 ~yl)oxy]phenyl} -5H-pyrrolo [3 ,2- 5 d]pyrknidin-4-atnine

To a solution of 4-cMoro-5-e1hyl-5H-pyrrolo[3,2-d]pyrknidine (85 mg) in l-methyl-2- pyrrolidone (0.94 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (150 mg). The title compound (67 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 29. i o ¹H-NMR (CDCl₃) δ 1.57 (3H, t, J= 7.4 Hz), 2.25 (3H, s), 2.53 (3H, s), 4.35 (2H, q, J= 7.4 Hz), 6.58 (IH, d, J= 3.0 Hz), 6.67 (IH, br s), 6.89 (IH, d, J= 8.7 Hz), 7.08 (IH, d, J= 8.5 Hz), 7.13 (IH, dd, J= 3.0, 8.7 Hz), 7.25 (IH, d, J= 3.0 Hz), 7.34 (IH, dd, J= 2.6, 8.7 Hz), 7.42 (IH, d, J= 2.5 Hz), 8.23 (IH, d, IH, J= 2.5 Hz), 8.50 (IH, s). Synthesis Example 35

Production of N-benzyl-N'-[3-(5H-pyrrolo[3,2-d]pyrrrrddin4-ylamino)phenyl]urea

To a solution of 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in l-methyl-2-pyrrolidone (1.3 mL), was added N-(3-aminophenyl)-N'-benzylurea (220 mg), and the mixture was heated to 140°C and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL), and extracted with a mixed solvent (30 mLx3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with 5 saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=100/0 -» 85/15). The object fraction was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound i o (97 mg) as pale-yellow powder crystals.

¹H-NMR (DMSOd₆) δ 4.32 (2H, d, J= 5.8 Hz), 6.47 (IH, s), 6.63 (IH, t, J= 5.8 Hz), 7.02 (IH, d, J= 8.4 Hz), 7.16-7.32 (6H, m), 7.62 (2H, d, J= 8.4 Hz), 7.98 (IH, s), 8.33 (IH, s), 8.63 (IH, s), 9.15 (IH, s), 11.22 (IH, s). Synthesis Example 36

Production of 4-{[4-({3-cWoro-4-[(3-fluorober)zyl)oxy]phenyl}amrno)-5H-pyrrolo[3,2- d]pyrimidm-5-yl]me1hyl}-N-(2-hydroxyethyl)benzamide

To a solution of 4-{[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2-- d]pvrimidin-5-yl]methyl}benzoic acid (126 mg) inN,N-dimethylformamide (1.2 mL) were added N-[3-(dimeihylamino)propyl]-N'-etliylcarbodiimide hydrochloride (72 mg) and 1- hydroxypyrrolidine-2;,5-dione (43 mg), and the mixture was stirred at room temperature for 3 hrs. To this reaction mixture was added dropwise a solution of 2-aminoethanol (23 mg) in a mixed solvent ofN,N-dimethylformamide (1.2 mL) and 10% aqueous sodium hydrogen carbonate (1.2 5 mL), and the mixture was stirred at room temperature for 48 hrs. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (25 mLx3). The organic layer was washed with saturated brine (25 mLx3), and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 — > 8/2). The object fraction i o was concentrated under reduced pressure. Chloroform /dϋsopropyl ether (1/4) was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (105 mg) as white powder crystals.

¹H-NMR PMSOd₆) δ 3.27 (2H, t, J= 5.9 Hz), 3.41-3.48 (2H, m), 4.68 (IH, t, J= 5.9 Hz), 5.21 (2H, s), 5.84 (2H, s), 6.56 (IH, d, J= 3.0 Hz), 7.06 (2H, d, J= 8.1 Hz), 7.08 (2H, t, J= 7.5 Hz), 7.27-7.35 is (3H, m), 7.46 (IH, dt, J= 5.8, 8.1 Hz), 7.64 (IH, d, J= 2.5 Hz), 7.73 (2H, d, J= 8.3 Hz), 7.82 (IH, d, J= 3.0 Hz), 8.27 (2H, s), 8.33 (IH, t, J= 5.4 Hz). Synthesis Example 37

Production of N-(3 -amino-3 -oxopropyl)-4- { [4-({3 -chloro-4-[(3 -fluorobenzyl)oxy]phenyl} amino)- 5H-pyrrolo[3,2-d]pyrimidin-5-yl]mefhyl}benzamide

The title compound (83 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 27 using 4-{[4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}airmo)-5H-pyrM^ acid (120 mg)

5 and β-alaninamide hydrochloride (45 mg).

¹H-NMR (DMSOd₆) δ 2.29 (IH, t, J= 7.2 Hz), 3.37-3.42 (4H, m), 5.21 (2H, s), 5.83 (2H, s), 6.56 (IH, d, J= 3.3 Hz), 6.80 (IH₅ br s), 7.06 (2H, d, J- 8.3 Hz), 7.18 (2H, t, J= 9.0 Hz), 7.29-7.34 (4H, m), 7.46 (IH, dt, J= 5.8, 7.9 Hz), 7.63 (IH, d, J= 2.4 Hz), 7.71 (2H, d, J= 8.3 Hz), 7.81 (IH, d, J= 3.2 Hz), 8.26 (IH, d, J= 3.3 Hz), 8.40 (IH, t, J= 5.7 Hz). i o Synthesis Example 38

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-ethoxyethyl)-5H-pyrrolo[3,2- d]pyrirnidin-4-amine

(i) Production of 4-cMoro-5-(2-e1hoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine 5 To a suspension of 4-chloro-5H-pyrrolo [3 ,2-d]pyrimidine (500 mg) in N₅N- dimethylformamide (4.5 mL) was added cesium carbonate (1324 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. 1 -Bromo-2-ethoxyethane (1016 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 hrs. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (120 mLx3). The organic layer was washed with saturated brine (100 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=85/15 —» 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (697 mg) as a pale-yellow oil.

¹H-NMR (CDCl₃) δ 1.13 (3H, t, J= 6.9 Hz), 3.43 (2H, q, J= 6.9 Hz), 3.78 (2H, t, J= 5.1 Hz), 4.67

(2H, t, J= 5.1 Hz), 6.71 (IH, d, J= 3.0 Hz), 7.59 (IH, d, J= 3.0 Hz), 8.70 (IH, s).

(ϋ) Production of N-{3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-ethoxyethyl)-5H-pyrrolo[3,2- d]pyritrudm-4-amine To a solution of 4-cMoro-5-(2-ethoxyemyl)-5H-pyrrolo[3,2-d]pyrirnidine (90 mg) in 1- methyl-2-pyrrolidone (0.7 mL), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (151 mg) was added, and the mixture was heated to 140°C and stirred for 7 hrs. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -> 8/2). The object fraction was concentrated under reduced pressure. The residue was recrystallized from dϋsopropyl ether, collected by filtration and dried under reduced pressure to give the title compound (90 mg) as pale-yellow needle crystals.

¹H-NMR (CDCl₃) δ 1.22 (3H, t, J= 7.0 Hz), 3.63 (2H, q, J= 7.0 Hz), 3.90 (2H, t, J= 4.4 Hz), 4.50 (2H, t, J= 4.4 Hz), 5.13 (2H, s), 6.61 (IH, d, J= 3.2 Hz), 6.94 (IH, d, J= 8.9 Hz), 7.01 (IH, 1, J= 8.1

Hz), 7.17-7.25 (3H, m), 7.35 (IH, dt, J= 5.6, 7.9 Hz), 7.47 (IH, dd, J= 1.3, 8.9 Hz), 7.64 (IH, d, J= 2.6 Hz), 8.48 (IH, s), 8.79 (IH, s).

Synthesis Example 39

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-me1hyl-5H-pyrrolo[3,2-d]pyrimidin- 5 4-amine

(i) Production of 4-cMoro-5-me1hyl-5H-pyrrolo[3,2-d]pyrimidine

To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrirnidine (320 mg) in N₅N- dimethylformarnide (2.0 mL), was added potassium carbonate (452 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. Iodomethane (444 mg) was i o added to the reaction mixture, and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (25 mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=80/20 -> 10/90). The

15 object fraction was concentrated under reduced pressure and dried to give the title compound (325 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 4.16 (3H, s), 6.70 (IH, d, J= 3.9 Hz), 7.42 (IH, d, J= 3.9 Hz), 8.69 (IH, s). (ϋ) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-methyl-5H-pyrrolo[3,2- d]pyrirrddin-4-amine To a solution of 4-cMoro-5-me1hyl-5H-pyiτolo[3,2-d]pyrirnidine (100 mg) in l-methyl-2- pyrrolidone (1.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (225 mg), and the mixture was heated to 140⁰C and stirred for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted 5 with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluenthexane/ethyl acetate=95/5 — >^■ 0/100). The object fraction was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of diisopropyl ether and chloroform, collected by filtration i o and dried under reduced pressure to give the title compound (121 mg) as a pale-purple powder crystals.

¹H-NMR (DMSO-de) δ 4.14 (3H, s), 5.24 (2H, s), 6.42 (IH, d, J= 3.0 Hz), 7.16-7.23 (2H, m), 7.29- 7.34 (2H, m), 7.44-7.56 (3H, m), 7.78 (IH, d, J= 2.4 Hz), 8.24 (IH, s), 8.36 (IH, s).

15 Synthesis Example 40

Production of 5-me1hyl-N-{3-memyl4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2- d]pvrimidm-4-amine

To a solution of 4-chloro-5-memyl-5H-pyiτolo[3,2-d]pyrirnidine (100 mg) in l-methyl-2- 0 pyrrolidone (1.0 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (192 mg). The title compound (106 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 39 (ii).

¹H-NMR (DMSOd₆) δ 2.17 (3H₅ s), 2.44 (3H, s), 4.15 (3H, s), 6.43 (IH₅ dd, J= 0.9, 3.0 Hz), 6.94 (IH, d, J= 8.4 Hz)₅ 7.18 (IH₅ dd, J= 3.0, 8.4 Hz)₅7.24 (IH₅ d, J= 8.7 Hz)₅7.51 (IH₅ d, J= 8.7 Hz), 7.56 (IH, d, J= 3.0 Hz), 8.17 (IH₅ d, J= 3.0 Hz), 8.25 (IH, d, J= 0.9 Hz)₅ 8.40 (IH, s), 8.63 (IH, s). Synthesis Example 41

Production of 2-[4-({3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2-d]pyrirmdin- 5-yl]ethanol (i) Production of 5-(2-{[tert-butyl(α%iethyl)sUyl]oxy}e1hyl)-4-cWoro-5H-pyrrolo[3₅2-d]pyrirnidine

To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrirnidine (307 mg) in N₅N- dimethylformamide (2.0 mL) was added cesium carbonate (977 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added tert-butyl(2-iodoethoxy)dimethylsilane (839 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine (30 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=85/l 5 — > 10/90). The obj ect fraction was concentrated under reduced pressure and dried to give the title compound (591 mg) as a white solid.

¹H-NMR (DMSO-de) δ 0.95 (9H, s), 4.10 (2H, t, J= 5.2 Hz), 4.76 (2H, t, J= 5.2 Hz), 6.87 (IH, d, J=

3.0 Hz), 7.57 (IH, d, J= 3.0 Hz), 8.85 (IH, s).

(ii) Production of 2-(4xUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethanol 5 To a solution of 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-chloro-5H-pyrrolo[3,2- d]pyrimidine (560 mg) intetrahydrofuran (1.7 mL), was added tetrabutylammonium fluoride (IM tetrahydrofuran solution) (2.69 mL) under ice-cooling, and the mixture was stirred for 4 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine (30 mLx3) and dried over anhydrous magnesium i o sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluentethyl acetate/methanol=10/0 -» 9/1). The object fraction was concentrated under reduced pressure and dried to give the title compound (391 mg) as a white solid.

¹H-NMR (CDCl₃) δ 2.13 (2H, td, J= 6.3, 12.6 Hz), 4.66 (2H, t, J= 6.3 Hz), 6.72 (IH, d, J= 3.0 Hz), s 7.57 (IH, d, J= 3.0 Hz), 8.70 (IH, s).

(iϋ) Production of 2-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl] ethanol

To a solution of 2-(4-cMoro-5H-pyiτolo[3,2-d]pyrirnidin-5-yl)ethanol (130 mg) in 1- methyl-2-pyrrolidone (1.3 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and0 the reaction mixture was stirred at 120⁰C for 2 hrs. The reaction mixture was allowed to cool to room temperature and ethyl acetate (20 mL) was added. The resultant precipitate was recrystaUized from a mixed solvent of hexane/methanol (3/7), collected by filtration and dried under reduced pressure to give the title compound (206 mg) as pale purple crystals. ¹H-NMR (DMSOd₆) δ 3.86 (2H, t, J= 4.3 Hz), 4.54 (2H, m), 5.24 (2H, s), 6.23 (IH, br s), 6.53 (IH, d, J= 3.2 Hz), 7.18 (IH, dt, J= 2.6, 8.1 Hz), 7.25 (IH, d, J= 9.0 Hz), 7.29-7.34 (2H, m), 7.43-7.51 (2H, m), 7.70 (IH, d, J= 3.2 Hz), 7.78 (IH, d, J= 2.6 Hz), 8.37 (IH, br s), 9.82 (IH, br s). Synthesis Example 42

Production of N-{3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyπ-olo[3,2-d]pyrirnidin-

4-amine

(i) Production of 4-cWoro-5-propyl-5H-pyrrolo[3,2-d]pyrrmidine

To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrirnidine (150 mg) in HN- i o dimethylformamide (1.6 mL) was added cesium carbonate (798 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 1-bromopropane (301 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL><3). The organic layer was washed with saturated brine (30 mLx3) and dried over anhydrous magnesium

15 sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=90/10 -> 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (161 mg) as a white solid. 1H-NMR (CDCl₃) δ 0.96 (3H, t, J= 7.5 Hz), 1.86-1.98 (2H, m), 4.44 (2H, t, J= 7.5 Hz), 6.73 (IH, t, J= 3.3 Hz), 7.48 (IH, d, J= 3.3 Hz), 8.70 (IH, s).

(ii) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-propyl-5H-pyrrolo[3,2- d]pyriimdin-4-arnine

To a solution of 4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine (80 mg) in l-methyl-2- 5 pyrrolidone (0.8 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 120⁰C for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL^χ3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the i o obtained residue was subjected to silica gel column chromatography (eluentethyl acetate/methanol=100/0 -» 95/5). The object fraction was concentrated under reduced pressure. To the residue was added a mixed solvent of diisopropyl ether and chloroform. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (96 mg) as a pale-purple powder.

25 ¹H-NMR (DMSOd₆) δ 0.85 (3H, t, J= 6.0 Hz), 1.81 (2H, q, J= 6.9 Hz), 4.42 (2H, t, J= 6.9 Hz), 5.18 (2H, s), 6.47 (IH, dd, J= 1.8, 3.0 Hz), 7.02 (IH, d, J= 8.7 Hz), 7.06 (IH, d, J= 2.4 Hz), 7.21- 7.49 (4H, m), 7.71 (IH, d, J= 2.4 Hz), 7.77 (IH, br s), 8.07 (IH, br s), 8.34 (IH, d, J= 2.1 Hz). Synthesis Example 43

Production of N-{3-cUoro-4-[(3-fluoroben2yl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3,2-d]pyriimdin-

4-amine

(i) Production of 4-cUoro-5-isobutyl-5H-pyrrolo[3,2-d]pyrirnidine

To a suspension of 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (150 mg) in N₃N- 5 dimethylformamide (1.6 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added l-bromo-2-methylpropane (336 mg), and the mixture was stirred at room temperature for 19 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine (30 mLx3) and dried over anhydrous i o magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=90/10 — >

20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as a white solid.

¹H-NMR (CDCl₃) δ 0.94 (6H, d, J= 6.6 Hz), 2.14-2.27 (IH, m), 4.26 (2H, d, J= 7.5 Hz), 6.72 (IH, d, is J= 2.4 Hz), 7.46 (IH, d, J= 2.4 Hz), 8.70 (IH, s).

(ϋ) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-isobutyl-5H-pyrrolo[3,2- d]pyrimidin-4-amine

The title compound (89 mg) was obtained as a pale-purple powder by the reaction in the same manner as in Synthesis Example 42 (ii) using a solution of 4-chloro-5-isobutyl-5H- 0 pyrrolo[3,2-d]pyrimidine (90 mg) in l-methyl-2-pyrrolidone (0.8 mL).

¹H-NMR (DMSO-dβ) δ 0.83 (6H, d, J= 6.3 Hz)₅2.08 (IH, m), 4.24 (2H, d, J= 7.5 Hz), 5.17 (2H, s),

6.47 (IH, d, J= 2.7 Hz), 7.02 (2H, d, J= 8.7 Hz), 7.22-7.29 (2H, m), 7.32 (IH, d, J= 3.0 Hz), 7.40

(IH, dt, J= 6.0, 8.1 Hz), 7.46 (IH, dd, J= 2.7, 9.0 Hz), 7.73 (IH, d, J= 2.7 Hz), 7.79 (IH, s), 8.09 (IH, br s).

Synthesis Example 44

Production of N-{3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(te1rahydrofuran-2-ylmetliyl)-5H- 5 pyrrolo[3,2-d]pyrimidin-4-amine

To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrixnidine (150 mg) in N₅N- dimethylformamide (1.0 mL) was added cesium carbonate (478 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was i o added 2-(bromomethyl)tetrahydrofuran (242 mg), and the mixture was stirred at room temperature for 26 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine (30 mL^χ3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl

15 acetate=90/10 -» 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (200 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ 1.47-1.64 (IH, m), 1.85-2.17 (3H, m), 3.75-3.90 (2H, m), 4.18-4.31 (IH, m), 4.42-4.53 (IH, m), 4.71 (IH, dd, J= 3.4, 14.6 Hz), 6.74 (IH, d, J= 3.0 Hz), 7.63 (IH, d, J= 3.0 Hz), 8.70 (IH, s). (ii) Production of N-{3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}-5-(tetrahydrofuran-2-ylmethyl)-5H- pyrrolo[3,2-d]pyrirrudin-4-amine

The title compound (139 mg) was obtained as white powder by the reaction in the same manner as in Synthesis Example 42 (ii) using a solution of 4-chloro-5-(tetmhydrofuran-2-ylme1hyl)- 5 5H-pyrrolo[3,2-d]pyrimidine (200 mg) in l-methyl-2-pyrrolidone (1.6 mL).

¹H-NMR(DMSOd₆) δ 1.56-1.65 (2H, m), 1.78-1.80 (IH, m), 1.97-2.07 (lH, m), 3.70 (2H, m), 4.17-4.19 (IH, m), 4.43 (IH, dd, J= 6.0, 15.0 Hz), 4.67 (IH, d, J- 13.8 Hz), 5.21 (2H, s), 7.14 (IH, dd, J= 8.1 Hz), 7.20 (IH, d, J= 8.1 Hz), 7.27-7.48 (4H, m), 7.61 (IH, d, J= 2.1 Hz), 7.78 (IH, d, J= 1.5 Hz), 8.25 (IH, d, J- 1.2 Hz), 8.60 (IH, d, J= 1.2 Hz), 9.03 (IH, s). i o Synthesis Example 45

Production of methyl 3 - { [4-( {3 -chloro-4-[(3 -fluorobenzyl)oxy]phenyl} amino)-5H-pyrrolo [3 ,2- d]pyrimidin-5-yl]methyl}benzoate

(i) Production of methyl 3-[(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)methyl]benzoate 15 To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (300 mg) inN,N- dimethylformamide (2.0 mL) was added cesium carbonate (955 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added methyl 3-(bromomethyl)benzoate (671 mg), and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was diluted with water (40 mL), and extracted with a mixed solvent (40 mL^χ3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed with saturated brine (120 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=80/20 — » 10/90). The object fraction was concentrated under reduced pressure. Chloroform/diisopropyl ether (4/1) was added to the residue, and the resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (319 mg) as a pale-brown powder.

¹H-NMR (CDCl₃) δ 3.90 (3H, s), 5.77 (2H, s), 6.82 (IH, d, J= 3.4 Hz), 7.19 (IH, dd, J= 1.2, 7.8 Hz), 7.41 (IH, t, J= 7.8 Hz), 7.54 (IH, d, J= 3.4 Hz), 7.82 (IH, s), 7.98 (IH, dt, J= 1.2, 7.8 Hz), 8.73 (IH, S).

(ii) Production of methyl 3-{[4-({3-cUoro-4-[(3-fluoroberizyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]methyl}benzoate

To a solution of methyl 3-[(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)methyl]benzoate (670 mg) in l-methyl-2-pyrrolidone (3.0 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (549 mg), and the reaction mixture was stirred at 120°C for 1.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (50 mL), and extracted with ethyl acetate (50 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluenthexane/ethyl acetate=9/l — > 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (1010 mg) as a yellow oil. 1H-NMR (CDCl₃) δ 3.93 (3H, s), 5.08 (2H, s), 5.60 (2H, s), 6.39 (IH, s), 6.67 (IH, d, J= 3.4 Hz),

6.82 (IH, d, J= 9.2 Hz), 7.01 (2H, dd, J= 2.6, 8.8 Hz), 7.16-7.40 (3H, m), 7.56 (IH, t, J= 7.8 Hz), 7.94 (IH, s), 8.09 (IH, d, J= 7.8 Hz), 8.47 (IH, s). Synthesis Example 46

Production of 3 - { [4-({3 -chloro-4-[(3 -fluorobenzyl)oxy]phenyl} amino)-5H-pyrrolo [3 ,2- 5 d]pyrimidin-5-yl]methyl}benzoic acid

To a solution of methyl 3-{[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]methyl}benzoate (800 mg) in a mixed solvent of tetrahydrofuran (4.0 mL) and methanol (4.0 mL) was added IN aqueous sodium hydroxide solution (4.0 mL), and the mixture was stirred at room temperature for 12 hrs. IN Hydrochloric acid (4.0 mL) and water (15 i o mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 30 min.

The resultant precipitate was collected by filtration, washed with water (10 mLx3) and diisopropyl ether (10 mLx3) and dried under reduced pressure (80°C) to give the title compound (610 mg) as a white powder.

¹H-NMR(DMSO^) δ 5.21 (2H, s), 5.86 (2H, s), 6.57 (IH, dd, J= 1.5, 3.3 Hz), 7.14-7.51 (8H, m), is 7.58 (IH, dd, J= 1.5, 2.4 Hz), 7.69 (IH, s), 7.78 (IH, d, J= 6.3 Hz), 7.84 (IH, d, J= 1.8 Hz), 8.27 (IH, d, J= 1.5 Hz), 8.30 (IH, s).

Synthesis Example 47

Production of 5-(2-e1hoxye11iyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine

To a solution of 4-cUoro-5-(2-e1hoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1- methyl-2-pyrrolidone (1.4 mL) was added 3-me1hyl-4-[(6-metiiylpyridin-3-yl)oxy]aniline (228 mg), and the reaction mixture was stirred at 120⁰C for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (40 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluenfchexane/ethyl acetate=90/10 -> 0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (191 mg) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 1.25 (3H, dt, J= 2.1, 7.2 Hz), 2.14 (3H, s), 2.52 (3H, s), 3.65 (2H, q, J= 7.2 Hz), 3.92 (2H, t, J= 4.5 Hz), 4.54 (2H, t, J= 4.5 Hz), 6.62 (IH, d, J= 3.0 Hz)₅ 6.91 (IH, d, J= 8.4 Hz), 7.11 (IH, dd, J= 2.7, 8.4 Hz), 7.20 (IH, d, J= 3.0 Hz), 7.40 (IH, dd, J= 2.7, 8.4 Hz), 7.51 (IH, d, J= 3.0 Hz), 8.26 (IH, dd, J= 0.6, 2.7 Hz), 8.50 (IH, s), 8.84 (IH, br s). Synthesis Example 48

Production of N-[3-cUoro-4-(pyridin-2-ylme1hoxy)phenyl]-5-(2-efhoxyethyl)-5H-pyrrolo[3,2- d]pyrirddm-4-arnine

To a solution of 4-cUoro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1- methyl-2-pyrrolidone (1.4 mL) was added 3-chloro-4-(pyridin-2-ylmethoxy)aniline (250 mg). The title compound (160 mg) was obtained as pale-yellow needle crystals by the reaction in the same manner as in Synthesis Example 42 (ii).

¹H-NMR (CDCl₃) δ 1.23 (3H, t, J= 7.2 Hz), 3.64 (2H, q, J= 7.2 Hz), 3.91 (2H, t, J= 7.2 Hz), 4.51 (2H, t, J= 7.2 Hz), 5.27 (2H, s), 6.12 (IH, s), 6.61 (IH, d, J= 3.3 Hz), 6.97 (IH, d, J= 8.7 Hz), 7.18 (IH, d, J= 3.3 Hz), 7.42 (IH, dd, J= 2.7, 8.7 Hz), 7.66 (IH, s), 7.69 (IH, d, J= 2.1 Hz), 7.76 (IH, dt, J= 1.5, 8.7 Hz), 8.49 (IH, s), 8.60 (IH, d, J= 4.5 Hz), 8.81 (IH, s). Synthesis Example 49

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5H-pyrrolo[3,2- d]pyrirnidin-4-amine (i) Production of 4-cMoro-5-(2-fluoroe1hyl)-5H-pyrrolo[3,2-d]pyrirnidine

To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrimidine (100 mg) in N₅N- dimethylformamide (0.6 mL) was added cesium carbonate (281 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was 5 added 1 -bromo-2-fluoroethane (124 mg), and the mixture was stirred at room temperature for 5 hrs.

The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mLx3).

The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=90/10 — > i o 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (110 mg) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 4.64-4.69(1H, m), 4.75-4.79(1H, m), 4.91 (2H, d, J= 5.1 Hz), 6.77 (IH, dd, J=

1.4, 3.4 Hz), 7.57 (IH, d, J= 3.4 Hz), 8.73 (IH, s).

(ii) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(2-fluoroethyl)-5H-pyrrolo[3,2- is d]pyrimidin-4-amine

The title compound (124 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 39 (ii) using a solution of 4-cWoro-5-(2-fruoroethyi)-5H- pyrrolo[3,2-d]pyrimidine (110 mg) in l-methyl-2-pyrrolidone (1.0 mL).

¹H-NMR (CDCl₃) δ 4.65(2H, dt, J= 4.0, 29.0 Hz), 4.90(2H, dt, J= 4.0, 47.2 Hz), 5.14 (2H, s), 6.65 0 (IH, d, J= 3.0 Hz), 6.93 (IH, d, J= 8.8 Hz), 7.04 (IH, d, J= 8.8 Hz), 7.21-7.41 (6H, m), 7.55 (IH, s),

8.48 (IH, s).

Synthesis Example 50

Production of 3-{[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]methyl}-N-(2-hydroxyethyl)benzainide

The title compound (93 mg) was obtained as white powder crystals by the reaction in the 5 same manner as in Synthesis Example 36 using 3-{[4-({3-chloro-4-[(3- fluoroberj2yl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyritrύdin-5-yl]me1hyl}benzoic acid (126 mg). 1H-NMR (DMSO-de) δ 3.26-3.48(4H, m), 4.71 (IH, t, J= 5.6 Hz), 5.21 (2H, s), 5.83 (2H, s), 6.55 (IH, d, J= 2.6 Hz), 7.06-7.52 (7H, m), 7.61-7.72 (4H, m), 7.80 (IH, d, J= 3.2 Hz), 8.26 (2H, s), 8.39 (IH, m). i o Synthesis Example 51

Production of ethyl [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidiri-5-yl] acetate

(i) Production of ethyl (4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate 5 To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) in N₅N- dimetiiylformamide (1.3 mL) was added cesium carbonate (615 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added ethyl bromoacetate (326 mg), and the mixture was stirred at room temperature for 2.5 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mLx3). The organic layer was washed with saturated brine (20 mL><3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=90/10 -> 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (210 mg) as white powder crystals. 1H-NMR (DMSOd₆) δ 1.29 (3H, t, J= 7.2 Hz), 4.27 (2H, q, J= 7.2 Hz), 5.21 (2H, s), 6.80 (IH, d, J= 3.3 Hz), 7.45 (IH, d, J= 3.3 Hz), 8.74 (IH, s).

(ii) Production of ethyl [4-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrrmidin-5-yl]acetate

To a solution of ethyl (4-cWoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetate (140 mg) in isopropyl alcohol (0.6 mL) was added 3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]aniline (188 mg), and the mixture was stirred in an oil bath at a temperature of 110°C for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (20 mL) and extracted with ethyl acetate (25 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=10/0 -» 9/1). The object fraction was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (210 mg) as white powder crystals. ¹H-NMR (CDCl₃) δ 1.35 (3H, t, J= 7.0 Hz), 2.25 (3H, s), 2.53 (3H, s), 4.35 (2H, q, J= 7.0 Hz), 4.96 (2H, s), 6.64 (IH, d, J= 3.4 Hz), 6.90 (IH, d, J= 8.8 Hz), 7.08 (IH, d, J= 1.8 Hz), 7.09 (IH, d, J= 2.6 Hz), 7.22 (IH, d, J= 3.4 Hz), 7.37 (IH, d, J= 8.8 Hz), 7.44 (IH, d, J= 2.6 Hz), 8.17 (IH, br s), 8.26 (IH, d, J= 1.8 Hz), 8.53 (IH, s). 5 Synthesis Example 52

Production of [4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]acetic acid

The title compound (101 mg) was obtained as white powder by the reaction in the same i o manner as in Synthesis Example 46 using ethyl [4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammo)-5H-pyiτolo[3,2-d]pyrimidin-5-yl]acetate (200 mg). 1H-NMR (DMSOd₆) δ 2.43 (3H, s), 2.51 (3H, s), 5.30 (2H, s), 6.49 (IH, s), 6.92 (IH, d, J= 8.8 Hz), 7.20-7.25 (2H, m), 7.37-7.44 (2H, m), 7.62 (IH, s), 8.17 (IH, s), 8.31 (IH, s). Synthesis Example 53

Production of 3 -[4-( {3 -chloro-4-[(3 -fluorobenzyl)oxy]phenyl} amino)-5H-pyrrolo [3 ,2-d]pyrimidin- 5-yl]propan-l-ol

(i) Production of 5-(3 - { [tert-butyl(dimethyl)silyl] oxy}propyl)-4-chloro-5H-pyrrolo [3 ,2- djpyrimidine

To a suspension of 4-cMoro-5H-pvrrolo[3,2-d]pyrimidine (400 mg) inN,N~ 5 ditnethylformamide (2.6 mL) was added cesium carbonate (957 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added (3-biOmopropoxy)(tert-butyl)dimethylsilane (979 mg), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine (30 mLx3) and dried i o over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=85/l 5 — > 10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (630 mg) as a white solid.

¹H-NMR (CDCl₃) δ 0.95 (9H, s), 2.83 (2H, t, J= 5.2 Hz), 4.10 (2H, t, J= 5.2 Hz), 4.76 (2H, t, J= 5.2 is Hz), 6.87 (IH, d, J= 2.8 Hz), 7.71 (IH, d, J= 2.8 Hz), 8.85 (IH, s).

(ϋ) Production of 3-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-l-ol

The title compound (320 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 41 (ϋ) using 5-(3-{[tert-buryl(dimethyl)silyl]oxy}propyl)-4- chloro-5H-pyrrolo[3,2-d]pyrimidine (600 mg). 0 ¹H-NMR (CDCl₃) δ 2.13 (2H, dt, J= 6.3, 12.6 Hz), 3.65 (2H, dd, J= 6.3, 10.2 Hz), 4.66 (2H, t, J=

6.3 Hz), 6.72 (IH, d, J= 3.0 Hz), 7.57 (IH, d, J= 3.0 Hz), 8.70 (IH, s).

(ϋi) Production of 3-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}aπiino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]propan-l-ol The title compound (180 mg) was obtained as pale purple crystals by the reaction in the same manner as in Synthesis Example 41 (ϋi) using 3-(4-cMoro-5H-pyπrolo[3,2-d]pyrimidin-5- yl)propan-l-ol (100 mg).

¹H-NMR (DMSO-dδ) δ 1.98 (2H₅ t, J= 6.0 Hz), 3.39 (2H, t, J= 6.0 Hz),4.66 (2H, t, J= 6.0 Hz), 5.30 5 (2H,s), 6.66 (IH, d, J= 3.2 Hz), 7.19 (IH, dt, J= 1.9, 8.3 Hz), 7.29-7.34 (3H, m), 7.44-7.52 (2H_S m), 7.72 (IH₅ d, J= 2.6 Hz), 8.00 (IH, d, J= 3.2 Hz), 8.66 (IH, s), 9.97 (IH, s). Synthesis Example 54

Production of N-(2-hydroxyemyl)-2-[4-({3-memyl-4-[(6-methylpyriα^-3-yl)oxy]phenyl}amino)- i o 5H-pyrrolo [3 ,2-d]pyrimidin-5-yl] acetamide

The title compound (38 mg) was obtained as white powder by the reaction in the same manner as in Synthesis Example 36 using [4-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenylammo}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)acetic acid (70 mg).

¹H-NMR (DMSO-dό) δ 2.17 (3H₅ s), 2.43 (3H₅ s), 3.24 (2H₅ dd, J= 5.6, 11.3 Hz), 3.47 (2H₅ dd, J= is 5.6, 11.3 Hz),4.86 (IH, t, J= 5.3 Hz)₅ 5.04 (2H₅ s), 6.49 (IH₅ d, J= 3.0 Hz)₅ 6.97 (IH, d, J= 8.5 Hz),

7.15 (IH, dd, J= 2.8, 8.5 Hz), 7.22 (IH₅ d, J= 8.5 Hz)₅7.54-7.57 (3H₅ m)₅ 8.16 (IH₅ d, J= 2.5 Hz),

8.30 (IH₅ s), 8.91 (IH, t, J= 5.6 Hz)₅ 10.10 (IH₅ s).

Synthesis Example 55

Production of N-{3-me1%l-4-[(6-me1iiylpyridin-3-yl)oxy]phenyl}-5-(4,4,4-trifluorobutyl)-5H- pyrrolo[3,2-d]pyrimidin-4-amine

(i) Production of 4-cUoro-5-(4,4,4-trffluorobutyl)-5H-pyrrolo[3,2-d]pyrirnidine 5 To a suspension of 4-chloro-5H-pyrrolo [3 ,2-d]pyrimidine (250 mg) in N,N~ dimethylformamide (1.6 mL) was added cesium carbonate (675 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 4-bromo-l,l,l-trifluorobutane (466 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 o mLx3). The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=9/l — > 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil. s ¹H-NMR (CDCl₃) δ 2.17 (4H, m), 4.57 (2H, t, J= 6.6 Hz), 6.76 (IH, d, J= 3.3 Hz), 7.47 (IH, d, J= 3.3 Hz), 8.72 (IH, s).

(ϋ) Production of N- {3 -methyl-4-[(6-methylpyridin-3 -yl)oxy]phenyl} -5-(4,4,4-trifluorobutyl)-5H- pyrrolo [3 ,2-d]pyrirrύdin-4-amine

The title compound (171 mg) was obtained as colorless oil by the reaction in the same o manner as in Synthesis Example 38 using 4-chloro-5-(4,4,4-trifluorobutyl)-5H-pyrrolo [3 ,2- djpyrimidine (150 mg).

¹H-NMR (CDCl₃) δ 2.00-2.17 (4H, m), 2.25 (3H₅ s), 2.53 (3H, s), 4.29 (2H, t, J= 6.9 Hz), 6.54 (IH, br s), 6.63 (IH, d, J= 3.2 Hz), 6.88 (IH, d, J= 8.5 Hz), 7.09 (IH, d, J= 8.5 Hz), 7.13 (IH, dd, J= 2.6, 8.5 Hz), 7.20 (IH, d, J= 2.6 Hz), 7.23 (IH, d, J= 3.2 Hz), 7.26 (IH, s), 7.32 (IH, d, J= 2.6 Hz), 8.23 5 (IH, d, J= 2.6 Hz), 8.54 (IH, s). Synthesis Example 56

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H- pyiτolo[3,2-d]pyrrmidm-4-amine i o (i) Production of 4-cUoro-5-[2-(2-e1hoxye1hoxy)ethyl]-5H-pyrrolo[3,2-d]pyrirnidine To a suspension of 4-cUoro-5H-pyrrolo[3,2-d]pyrirnidine (300 mg) inN,N- dimethylformamide (2.0 mL) was added cesium carbonate (728 mg) under ice-cooling, and the mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added l-bromo-2-(2-ethoxyethoxy)ethane (496 mg), and the mixture was stirred at room

15 temperature for 20 hrs. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL><3). The organic layer was washed with saturated brine (20 mLx3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluenthexane/ethyl acetate=9/l — > 0/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (440 mg) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 1.17 (3H, t, J= 7.1 Hz), 3.40-3.58 (6H, m), 3.87 (2H, t, J= 5.1 Hz), 4.69 (2H₅1, J= 5.1 Hz), 6.70 (IH, d, J= 3.3 Hz), 7.63 (IH, d, J= 3.3 Hz), 8.69 (IH, s). (ϋ) Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-[2-(2-ethoxyethoxy)ethyl]-5H- 5 pyαolo[3,2-d]pyrirnidin-4-amine

To a solution of 4-cUoro-5-[2-(2-ethoxye1hoxy)e1hyl]-5H-pyrrolo[3,2-d]pyrirnidine (150 mg) in l-methyl-2-pyrrolidone (1.1 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg), and the reaction mixture was stirred at 120⁰C for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), o and extracted with ethyl acetate (30 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=100/0 — > 95/5). The object fraction was concentrated under reduced pressure and dried to give the title compound (146 mg) as a colorless oil. 1H-NMR (CDCl₃) δ 1.09 (3H, t, J=6.9 Hz), 3.36 (2H, q, J=6.9 Hz), 3.51 (2H, t, J=4.2 Hz), 3.71 (2H, t, J=4.5 Hz), 3.98 (2H, t, J=4.5 Hz), 4.51 (2H, t, J=4.2 Hz), 5.24 (2H,s), 6.60 (IH, d, J=3.0 Hz), 6.91 (2H, d, J=8.8 Hz), 7.00 (2H, t, J=7.2 Hz), 7.17-7.37 (2H, m), 7.50 (IH, dd, J=2.7, 8.8 Hz), 7.68 (IH, d, J=3.0 Hz), 8.47 (IH, s), 8.68 (IH, s). Synthesis Example 57

Production of 5-[2-(2-ethoxyethoxy)ethyl]-N- {3 -mefhyl-4-[(6-methylpyridin-3 -yl)oxy]phenyl}-5H- pyrrolo [3 ,2-d]pyrirnidin-4-aniine

The title compound (98 mg) was obtained as colorless oil by the reaction in the same manner as in Synthesis Example 47 using 4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2- djpyrimidine (150 mg).

¹H-NMR (DMSOd₆) δ 0.93 (3H, t, J= 7.0 Hz), 2.24 (3H, s), 2.74 (3H, s), 3.23 (2H, q, J= 7.0 Hz), 3.37-3.40 (2H, m), 3.56-3.59 (2H, m), 3.86 (2H, t, J=4.5 Hz), 4.89 (2H, t, J=4.5 Hz),6.72 (IH, d, J=3.0 Hz), 7.22 (IH, d, J=8.7 Hz), 7.58-7.66 (2H, m), 7.91 (IH, d, J=8.7 Hz), 8.05 (IH, t, J=3.0 Hz), 8.09 (IH, d, J=3.0 Hz), 8.36 (IH, d, J=2.8 Hz), 8.73 (IH, s), 10.07 (IH, br s). Synthesis Example 58

Production of 2- [4-( {3 -methyl-4-[(6-methylpyridin-3 -yl)oxy]phenyl} amino)-5H-pyrrolo [3 ,2- d]pyrimidin-5-yl]ethanol

The title compound (241 mg) was obtained as white powder crystals by the reaction in the same manner as in Synthesis Example 47 using 2-(4-cUoro-5H-pyiτolo[3,2-d]pyrimidin-5- yl)ethanol (250mg).

¹H-NMR CDMSO-Cl₆) δ 2.17 (3H, s), 2.43 (3H, s), 3.87 (2H, t, J= 4.5 Hz), 4.52 (2H, t, J= 4.5 Hz), 6.27 (IH, br s), 6.48 (IH, dd, J= 1.6, 3.0 Hz), 6.97 (IH, d, J= 9.6 Hz), 7.16 (IH, ddd, J= 1.6, 3.0, 8.7 Hz), 7.23 (IH, d, J= 8.4 Hz), 7.53 (2H, br s), 7.63 (IH, dd, J= 1.6, 3.0 Hz), 8.17 (IH₅ d, J= 3.0 Hz), 8.28 (IH, d, J= 1.6 Hz), 9.66 (IH, br s). Synthesis Example 59

Production of 4- { 3-methyl-4-[(6-methylpyridin-3 -yl)oxy]phenyl} -5,6-dihydro-4H-pyrrolo [3 ,2, 1 - dejpteridine To a suspension of 2-[4-({3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrirnidin-5-yl]ethanol (50 mg) andtributylphosphine (54 mg) in toluene (2.5 mL) was added l,r-[(E)-diazene-l,2-diyldicarbonyl]dipiperidine (67 mg), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mLx3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluentethyl acetate/methanol=100/0 — » 90/10). The object fraction was concentrated under reduced pressure and dried to give the title compound (36 mg) as a white powder. 1H-NMR (CDCl₃) δ 2.29 (3H, s), 2.54(3H, s), 4.21 (2H, t, J= 5.1 Hz), 4.41 (2H, t, J= 5.1 Hz),6.59 (IH, d, J= 2.7 Hz), 6.92 (IH, d, J= 8.4 Hz), 7.11 (IH, d, J= 8.4 Hz), 7.18 (IH, dd, J= 2.7, 8.4 Hz), 7.23-7.27 (2H, m), 7.38 (IH, d, J= 2.7 Hz), 8.26 (IH, d, J= 2.7 Hz), 8.49 (IH, s). Synthesis Example 60

5 Production of ethyl 3-(5H-pyrrolo[3,2-d]pyriniidin-4-ylaniino)benzoate

A mixture of 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (2.78 g), ethyl 3-aminobenzoate (4.49 g) and 1 -methyl-2-pyrrolidone (20 mL) was stirred at 12O⁰C for 1.5 hrs. To the reaction mixture were added ethyl acetate, water and saturated aqueous sodium hydrogen carbonate solution. The insoluble material was filtered off, and the ethyl acetate layer was separated. The aqueous layer was i o extracted with ethyl acetate, and the mixed ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The filtered insoluble material was suspended in methanol and ethyl acetate and saturated brine were added. The ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixed ethyl acetate layer was concentrated under reduced pressure and the obtained

15 residue was purified by silica gel column chromatography (eluent, ethyl acetate) and crystallized from methanol-acetone-dϋsopropyl ether to give the title compound (2.85 g) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 1.39 (3H, t, J= 7.2 Hz), 4.37 (2H₅ q, J= 7.2 Hz), 6.51 (IH₅ d, J= 3.3 Hz), 7.28- 7.32 (IH, m), 7.42 (IH₅1, J= 8.0 Hz), 7.70 (IH₅ d, J= 7.8 Hz), 8.09 (IH₅ s), 8.29 (IH, d₅ J= 8.1 Hz)₅ 0 8.49 (IH₅ m). Synthesis Example 61

Production of 3-(5H-pyrrolo[3,2-d]pyriroidin-4-ylamino)benzoic acid

A mixture of ethyl 3-(5H-pyrrolo[3,2-d]pyrirrήdin-4-ylamino)benzoate (3.34 g), IN aqueous sodium hydroxide solution (25 mL) and methanol (50 mL) was stirred overnight at room temperature. To the reaction mixture was added IN hydrochloric acid (25 mL), and methanol was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with water to give the title compound (3.09 g)as a pale-brown powder. 1H-NMR (DMSO-d_δ) δ: 6.50 (IH, m), 7.49 (IH, t, J= 7.8 Hz), 7.60 (IH, d, J= 7.8 Hz), 7.69 (IH, t, J= 2.7 Hz), 8.25 (IH, d, J= 7.8 Hz), 8.39 (IH, s), 8.43 (IH, s), 9.54 (IH, s), 11.24 (IH, s), 13.01 (IH, br). Synthesis Example 62

Production of N-[3-(piperidin-l-ylcarbonyl)phenyl]-5H-pyiτolo[3,2-d]pyrimidin4-arnine

A mixture of 3-(5H-pyrrolo[3,2-d]pyrirrddin-4-ylarnino)benzoic acid (153 mg), piperidine (0.078 mL), l-[3-(dimemylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) andN,N- dimethylformamide (10 mL) was stirred at room temperature for 2 hrs. Piperidine (0.078 mL) and l-[3-(drmethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg) were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole (138 mg) was added, and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 — > 20:80). Diisopropyl ether was added and the precipitate was collected by filtration to give the title compound (78 mg) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 1.56 (2H, m), 1.73 (4H, m), 3.42 (2H, m), 3.83 (2H, m), 6.58 (IH, d, J= 2.4 Hz), 6.90 (IH, d, J= 7.5 Hz)₅7.18-7.22 (IH, m), 7.23 (IH₅ s), 7.30 (IH, t, J= 2.4 Hz)₅7.88 (IH₅ d, J= 8.3 Hz), 8.47 (IH₅ s), 8.70 (IH₅ s), 10.71 (IH₅ s). Synthesis Example 63

Production of N-[3 -(1hiomorpholin-4-ylcarbonyl)phenyl]-5H-pyirolo [3₅2-d]pyrrmidin-4-amrne A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin4-ylamino)benzoic acid (153 mg), thiomorpholine (0.091 mL), l-[3-(dimethylamino)propyl]-3-ethylcarbodrirnide hydrochloride (173 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 hrs. Tbiomorpholine (0.030 mL) and l-[3-(dimethylammo)propyl]-3-ethylcarbodiirnide hydrochloride (173 mg) were added and the mixture was stirred for 1 hr. 1-Hydroxybenzotriazole (138 mg) was added, and the mixture was stirred for 3 days. Saturated brine was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 — » 20:80). Diisopropyl ether was added and the precipitate was collected by filtration. The precipitate was dissolved in ethyl acetate containing methanol, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue and the precipitate was collected by filtration to give the title compound (82 mg) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 2.65 (2H, m), 2.77 (2H, m), 3.78 (2H, m), 4.05 (2H, m), 6.59 (IH, d, J= 3.0 Hz), 6.98 (IH, d, J= 6.9 Hz), 7.33 (IH, d, J= 7.8 Hz), 7.38 (IH, d, J= 3.0 Hz), 7.53 (IH, s), 7.95 (IH, br), 8.48 (IH, s).

Synthesis Example 64

Production of N-{3-[(4-berizylpiperidin4-yl)carbonyl]phenyl}-5H-pvrrolo[3,2-d]pyrirriidin-4- amine A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), 4- benzylpiperidine (158 mg), l-[3-(dime1hylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylforrnamide (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, water was added and extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=O:100 — > 20:80). The obtained product was dissolved in ethyl acetate containing methanol and tetrahydrofuran, washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was 5 evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The precipitate was collected by filtration to give the title compound (201 mg) as a pale-brown powder. 1H-NMR (CDCl₃) δ: 1.10-2.00 (6H, m), 2.86 (2H, d, J= 6.9 Hz), 2.75-3.05 (2H, m), 3.78-3.91 (IH, m), 4.68-4.82 (IH, m), 6.55 (IH, d, J= 3.0 Hz), 6.90 (IH, d, J= 7.5 Hz)₅7.10-7.33 (TH, m), 7.40 (IH, s), 7.72 (IH, d, J= 8.1 Hz), 8.45 (IH, s), 8.77 (IH, s), 10.83 (IH, s). i o Synthesis Example 65

Production of N-benzyl-3 -(5H-pyrrolo [3 ,2-d]pyrirrddin-4-ylamino)benzamide

A mixture of 3-(5H-pvnOlo[3,2-d]pyrinddin-4-ylarnino)benzoic acid (153 mg), benzylamine (96 mg), l-[3-(dimethylamino)propyl]-3-e1hylcarbodiirnide hydrochloride (173 mg), s 1 -hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the0 obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 -» 50:50). Ethyl acetate and diethyl ether were added and the precipitate was collected by filtration to give the title compound (128 mg) as a colorless powder. 1H-NMR (DMSOd₆) δ: 4.50 (2H, d, J= 6.0 Hz), 6.49 (IH, m), 7.21-7.38 (5H, m), 7.46 (IH, t, J= 8.0 Hz), 7.55 (IH, d, J= 8.1 Hz), 7.68 (IH, t, J= 3.0 Hz), 8.19 (IH, s), 8.26 (IH, d, J= 8.0 Hz), 8.37 5 (IH, s), 9.06 (IH, t, J= 6.0 Hz), 9.41 (IH, s), 11.13 (IH, s). Synthesis Example 66

Production of [2-(TDenzyloxy)-5-(5H-pyrrolo[3,2-d]pyrirnidin-4-ylamino)phenyl]methanol A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (307 mg), [5-amino-2- i o (benzyloxy)phenyl]methanol (459 mg) and N,N-dimethylformamide (10 mL) was stirred at 80°C for 4 hrs. The reaction mixture was concentrated under reduced pressure, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate containing tetrahydrofuran. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified

15 by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 -» 30:70). Ethanol and ethyl acetate were added and the precipitate was collected by filtration to give the title compound (279 mg) as a brown powder.

¹H-NMR (DMSOd₆) δ: 4.60 (2H, d, J= 5.5 Hz), 5.12 (2H, s), 5.17 (IH, t, J= 5.5 Hz), 6.45 (IH, m), 7.03 (IH, d, J= 8.8 Hz), 7.29-7.51 (5H, m), 7.62 (IH, t, J= 2.9 Hz), 7.65 (IH, d, J= 2.7 Hz), 7.93 (IH, dd, J= 8.8, 2.7 Hz), 8.29 (IH, s), 9.08 (IH, s), 11.05 (IH, s).

Synthesis Example 67

Production of N-[4-(ben2yloxy)-3-me1hoxyphenyl]-5H-pyπ:olo[3,2-d]pyrirmdm-4-amine 5 A mixture of 4-chloro-5H-pyrrolo[3,2-d]pyrirnidine (200 mg), 4-(benzyloxy)-3- methoxyaniline (298 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 80⁰C for 4 hrs.

Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried i o over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=10:80 -» 20:80) and recrystallized from methanol-ethyl acetate to give the title compound

(269 mg) as a pale-gray powder.

¹H-NMR (DMSO-de) δ: 3.82 (3H, s), 5.06 (2H, s), 6.45 (IH, m), 7.03 (IH, d, J= 8.9 Hz), 7.30-7.49 is (6H, m), 7.51 (IH, d, J= 2.5 Hz), 7.63 (IH, t, J= 2.9 Hz), 8.30 (IH, s), 9.07 (IH, s), 11.06 (IH, s).

Synthesis Example 68

Production of N-[4-φenzyloxy)-3-cUorophenyl]-5H-pyixolo[3,2-d]pyriniidin4-amine

A mixture of 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (200 mg), 4-(benzyloxy)-3- chloroaniline (365 mg) and l-methyl-2-pyrrolidone (3 mL) was stirred at 80°C for 4 hrs. Methanol and activated carbon were added to the reaction mixture and the mixture was stirred. The activated carbon was filtered off, aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 —> 15:75) and recrystallized from ethanol-ethyl acetate to give the title compound (226 mg) as a pale-brown powder.

¹H-NMR (CDCl₃) δ: 5.15 (2H, s), 6.56 (IH, s), 6.98 (IH, d, J= 8.9 Hz), 7.28-7.43 (4H, m), 7.48 (2H, d, J= 7.5 Hz), 7.69 (IH, d, J= 8.9 Hz), 7.80 (IH, d, J= 2.6 Hz), 8.50 (IH, s), 8.63 (IH, s), 10.56 (IH, s). Synthesis Example 69

Production of ethyl 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate

A mixture of ethyl 4-cHoro-5H-pyrrolo[3,2-d]pyrimidine (461 mg), 5-amino-2- phenoxybenzoate (926 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 8O⁰C for 2 hrs. 5 Ethanol, water and activated carbon were added to the reaction mixture and the mixture was stirred.

The activated carbon was filtered off, and the solvent was evaporated under reduced pressure.

Aqueous sodium hydrogen carbonate solution was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the i o obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 ->• 20:80) and recrystallized from ethanol-ethyl acetate to give the title compound

(572 mg) as a colorless powder.

¹H-NMR (CDCl₃) δ: 1.12 (3H, t, J= 7.1 Hz), 4.19 (2H, q, J= 7.1 Hz), 6.57 (IH, d, J= 3.0 Hz), 6.84

(2H, d, J= 7.7 Hz), 6.95 (IH, d, J= 8.9 Hz), 7.00 (IH, t, J= 7.3 Hz), 7.19-7.29 (2H, m), 7.34 (IH, d, is J= 3.0 Hz), 7.80 (IH, dd, J= 8.9, 2.8 Hz), 8.00 (IH, d, J= 2.8 Hz), 8.67 (IH, s), 8.87 (IH, s), 10.89

(IH, s).

Synthesis Example 70

Production of 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrinτidin-4-ylanτino)benzoic acid

A mixture of ethyl 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoate (899 mg), IN aqueous sodium hydroxide solution (5 mL) and methanol (15 mL) was stirred at 60°C for 1.5 hrs. To the reaction mixture was added IN hydrochloric acid (5 mL), and methanol was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with water and acetone to give the title compound (768 mg) as a pale-brown powder. 1H-NMR (DMSOd₆) δ: 6.50 (IH, m), 6.89 (2H, d, J= 7.7 Hz), 7.04 (IH, t, J= 7.3 Hz), 7.12 (IH, d, J= 8.9 Hz), 7.33 (2H, t, J= 8.0 Hz), 7.69 (IH, t, J= 2.9 Hz), 8.16 (IH, dd, J= 8.9, 2.9 Hz), 8.31 (IH, d, J= 2.9 Hz), 8.37 (IH, s), 9.46 (IH, s), 11.11 (IH, s), 12.95 (IH, br). Synthesis Example 71

Production of [2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrimidin-4-ylarnino)phenyl]methanol

To a solution of 2-phenoxy-5-(5H-pyrrolo[3,2-d]pyrrrrύdin-4-ylamino)benzoic acid (173 mg) in N,N-dimethylformamide (5 mL) was added 1,1' -carbonyldϋmidazole (97 mg) and the mixture was stirred at room temperature for 1 hr. Sodium borohydride (38 mg) was added to the reaction mixture at room temperature, and methanol (1 mL) was added dropwise. After stirring overnight at room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=O: 100 — > 20:80) and crystallized from methanol-ethyl acetate, to give the title compound (44 mg) as a colorless powder.

¹H-NMR (DMSOd₆) δ: 4.50 (2H, d, J= 5.1 Hz), 5.28 (IH, t, J= 5.1 Hz), 6.48 (IH, m), 6.90 (2H, d, J= 7.7 Hz), 6.96 (IH, d, J= 8.7 Hz)₅7.06 (IH, t, J= 7.3 Hz), 7.30-7.40 (2H, m), 7.66 (IH, % J= 2.9 Hz), 7.85 (IH, d, J= 2.7 Hz), 8.04 (IH, dd, J= 8.7, 2.7 Hz), 8.34 (IH, s), 9.28 (IH, s), 11.11 (IH, s). Synthesis Example 72

Production of 6-(2-furyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine

(i) Production of 2-cyano-l-(2-furyl)vinyl 4-methylbenzenesulfonate

To a mixture of 3-(2-furyl)-3-oxopropanenitrile (5.29 g), p-toluenesulfonyl chloride (9.00 g) and dichloromethane (60 mL) was added dropwise triethylamine (5.99 g) under ice-cooling. After stirring under ice-cooling for 1.5 hrs, the mixture was diluted with dichloromethane (100 mL). The mixture was washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9:l -> 3:1) to give the title compound (10.48 g) as amixture of (E)~form and (Z)-form (3:1).

¹H-NMR (CDCl₃) δ 2.47 (3/4H, s), 2.49 (9/4H, s), 5.27 (1/4H, s), 5.63 (3/4H, s), 6.47 (1/4H, m), 6.53 (3/4H, m), 6.86 (1/4H, d, J= 3.6 Hz), 6.95 (3/4H, d, J= 3.6 Hz), 7.38 (1/2H, d, J= 7.8 Hz), 7.42 (3/2H, d, J= 7.8 Hz), 7.51 (3/4H, m), 7.55 (1/4H, m), 7.83 (1/2H, d, J= 7.8 Hz), 7.97 (3/2H, d, J= 7.8 Hz). (ϋ) Production of ethyl 3-amitio-5-(2-furyl)-lH-pyrrole-2-carboxylate

To a solution of 2-cyano-l-(2-furyl)vinyl 4-methylbenzenesulfonate (10.48 g) and diethyl aminomalonate hydrochloride (7.67 g) in amixed solvent of ethanol (120 mL)-tetrahydrofuran (64 mL) was added dropwise a solution (36.9 mL) of 20% sodium ethoxide in ethanol under ice- cooling. After stirring at room temperature for 12 hrs, the reaction mixture was poured into ice water (350 mL) and adjusted to pH 7 with IN hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (150 mLx3). The organic layers were combined, washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=3 : 1 -> 1 : 1) and the obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (2.66 g). 1H-NMR (CDCl₃) δ 1.37 (3H, t, J= 7.0 Hz)₅4.34 (2H, q, J= 7.0 Hz), 4.37 (2H, br s), 5.93 (IH, d, J= 2.7 Hz), 6.45 (IH, dd, J= 3.6, 1.8 Hz), 6.49 (IH, d, J= 3.6 Hz), 7.41 (IH, d, J= 1.8 Hz), 8.35 (IH, br s). (iii) Production of 6-(2-fiiryl)-4,5-dihydro-3H-pyiτolo[3,2-d]pyrimidin-4-one

To a solution of ethyl 3-ammo-5-(2-furyl)-lH-pyrrole-2-carboxylate (2.58 g) in ethanol (35 mL) was added fonnamidine acetate (1.83 g), and the mixture was heated under reflux for 18 hrs.

After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 60⁰C to give the title compound (2.26 g).

¹H-NMR PMSOd₆) δ 6.58 (IH, d, J= 2.1 Hz), 6.61 (IH, dd, J= 3.5, 2.1 Hz), 7.08 (IH, m), 7.76 5 (IH, m), 7.80 (IH, d, J= 3.5 Hz), 11.91 (IH, br s), 12.50 (IH, br s).

(iv) Production of 4-cMoro-6-(2-furyl)-5H-pyiτolo[3_J2-d]pyrirnidine

A mixture of 6-(2-fluyl)-4,5-αihydro-3H-pyrrolo[3,2-d]pyrirnidin-4-one (2.20 g) and phosphoryl chloride (10.7 g) was stirred at 100⁰C for 20 min, dioxane (30 mL) was added, and the mixture was stirred at 100⁰C for 3 hrs. After concentration under reduced pressure, saturated i o aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate-acetone (155 mLx4). The organic layers were combined, washed with saturated brine

(100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate-diethyl ether, and dried under reduced pressure at 60⁰C to give the title compound (2.19 g). is ¹H-NMR PMSOd₆) δ 6.74 (IH, dd, J= 3.6, 2.1 Hz), 6.95 (IH, d, J= 1.8 Hz), 7.37 (IH, dd, J= 3.6,

0.6 Hz), 7.95 (IH, dd, J= 2.1, 0.6 Hz), 8.60 (IH, s), 12.71 (IH, br s).

(v) Production of 6-(2-fuiyl)-N-{3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidm-4-amine

A mixture of 4-cMoro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-methyl-4-[(6- 0 methylpyridin-3-yl)oxy]aniline (161 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at

140⁰C for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mL^χ2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=l : 1 -» 0: 1). The object traction was concentrated under reduced pressure. Chloroform - diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60⁰C to give the title compound (114 mg). 1H-NMR (DMSO-dδ) δ 2.21 (3H, s), 2.48 (3H, s), 6.72 (IH, dd_> J= 3.3, 1.8 Hz), 6.78 (IH, d, J- 1.8 Hz)₅ 6.98 (IH, d, J= 8.4 Hz), 7.02 (IH, d, J= 3.6 Hz), 7.17 (IH, dd, J= 8.4, 2.7 Hz), 7.22 (IH, d, J= 8.4 Hz), 7.74 (IH, dd, J= 8.4, 2.7 Hz), 7.80 (IH, d, J= 2.1 Hz), 7.92 (IH, dd, J= 1.8, 0.9 Hz), 8.16 (IH, dd, J= 2.7, 0.9 Hz), 8.33 (IH, s), 9.17 (IH, br s), 11.67 (IH, br s). Synthesis Example 73

Production of N-{3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}-6-(2-furyl)-5H-pyrrolo[3,2- d]pyrrmidin-4-arnine

A mixture of 4-cMoro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (110 mg), 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (189 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140°C for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mLx2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:l -> 1:1). The object fraction was concentrated under reduced pressure. Chloroform - diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60⁰C to give the title compound (122 mg).

¹H-NMR (DMSO-ds) δ 5.23 (2H, s), 6.71 (IH, dd, J= 3.3, 2.1 Hz), 6.78 (IH, d, J= 2.1 Hz)₅ 7.02 (IH, d, J= 3.3 Hz), 7.18 (IH, m), 7.25 (IH, d, J= 9.0 Hz)₅ 7.28-7.33 (2H, m), 7.46 (IH₅ m), 7.57 (IH, dd, J= 9.0, 3.0 Hz)₅ 7.92 (IH₅ d, J= 1.8 Hz), 8.18 (IH, d, J= 2.4 Hz), 8.33 (IH, s), 9.18 (IH, br s), 11.61 (IH, br s). Synthesis Example 74

Production of N-[3-cMoro4-(pyridin-2-ylmethoxy)phenyl]-6-(2-furyl)-5H-pyrrolo[3 ,2- d]pyrirrύdin-4-amine

A mixture of 4-cMoro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrirnidine (80 mg), 3-chloro-4- (pyridin-2-ylmethoxy)aniline (94 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140°C for 2 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (30 mLx2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=l :1 — > 0:1). The object fraction was concentrated under reduced pressure. Chloroform - diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 6O⁰C to give the title compound (71 mg). ¹H-NMR(DMSO-Cl₆) δ 5.27 (2H, s), 6.72 (IH, m), 6.78 (IH, d, J= 1.2 Hz), 7.02 (IH, d, J= 3.3 Hz), 7.26 (IH, d, J= 9.0 Hz), 7.36 (IH, m), 7.53-7.59 (2H, m), 7.81 (IH, d, J= 8.1 Hz), 7.91 (IH, s), 8.21 (IH, d, J= 2.4 Hz), 8.34 (IH, s), 8.59 (IH, d, J= 5.1 Hz), 9.19 (IH, br s), 11.62 (IH, br s).

Synthesis Example 75

Production of 4-[4-({3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-6-yl]benzoic acid hydrochloride

(i) Production of methyl 4-(2-cyano-l-{[(4-methylphenyl)sulfonyl]oxy}vinyl)benzoate

To a mixture of methyl 4-(cyanoacetyl)benzoate (10.29 g), p-toluenesulfonyl chloride (11.58 g) and dichloromethane (110 mL) was added dropwise triethylamine (7.68 g) underice- cooling. After stirring under ice-cooling for 2.5 hrs, the mixture was diluted with dichloromethane (100 mL), washed with water (150 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:methyl acetate=9: 1 -> 1 : 1) to give the title compound (17.60 g) as a mixture of (E)-form and (Z)-form (6:5).

¹H-NMR (CDCl₃) δ 2.44 (18/1 IH, s), 2.47 (15/1 IH, s), 3.94 (18/1 IH, s), 3.95 (15/1 IH, s), 5.66

(6/1 IH, s), 5.68 (5/1 IH, s), 7.33 (12/1 IH, d, J= 7.8 Hz), 7.38 (10/1 IH, d, J= 7.8 Hz), 7.62-8.09 (6H, m).

(ii) Production of ethyl 3-amino-5-[4-(ethoxycarbonyl)phenyl]-lH-pyrrole-2-carboxylate

To a suspension of methyl 4-(2-cyano-l-{[(4-methylphenyl)sulfonyl]oxy}vrnyl)benzoate (17.5 g) and diethyl aminomalonate hydrochloride (10.36 g) in a mixed solvent of ethanol (165 mL)-tetrahydrofuran (80 mL) was added dropwise a solution (50 mL) of 20% sodium ethoxide in ethanol under ice-cooling. After stirring under ice-cooling for 1 hr, the mixture was stirred at room temperature for 21 hr. the reaction mixture was poured into ice water (400 mL) and adjusted to pH 7 with IN hydrochloric acid. The organic solvent was evaporated under reduced pressure, and the residue was extracted with ethyl acetate (250 mLx3). The organic layers were combined, washed with saturated brine (150 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2: 1 -> 1 : 1) and the obtained solid was recrystallized from ethyl acetate to give the title compound (4.76 g).

¹H-NMR (CDCl₃) B 1.36-1.43 (6H, m)₅4.31-4.42 (6H, m), 6.11 (IH, d, J= 3.0 Hz), 7.55 (2H, d, J=

8.4 Hz), 8.04 (2H, d, J= 8.4 Hz), 8.40 (IH, br s).

(ϋi) Production of ethyl 4-(4-oxo-4,5-α^ydro-3H-pyrrolo[3₅2-d]pyrirnidin-6-yl)benzoate

A mixture of ethyl 3-amino-5-[4-(ethoxycarbonyl)phenyl]-lH-pyrrole-2-carboxylate (3.36 g), formamidine acetate (1.74 g) and ethanol (60 mL) was heated under reflux for 15 hrs. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 6O⁰C to give the title compound (2.97 g).

¹H-NMR (DMSOd₆) δ 1.34 (3H, 1, J= 7.1 H²X ⁴-³³ (^2H> % ^{J= lλ} Hz), ^7M (^1H> ^s)> ^7M (^1H> 4 J= 2.7 Hz), 8.00 (2H, d, J= 8.1 Hz), 8.11 (2H, d, J= 8.1 Hz), 11.97 (IH, br s), 12.64 (IH, br s). (iv) Production of ethyl 4-(4-cWoro-5H-pyπ-olo[3,2-d]pyrijmidin-6-yl)benzoate hydrochloride

A mixture of ethyl 4-(4-oxo4,5-dihyώ:o-3H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate (2.97 g) and phosphoryl chloride (16.45 g) was stirred at 110⁰C for 1 hr, dioxane (10 mL) was added and the mixture was heated under reflux for 4 hrs. After concentration under reduced pressure, ethanol (30 mL) was added to the residue and, after stirring at room temperature for 30 min, the precipitated solid was collected by filtration. The solid was washed with ethanol and dried under reduced pressure at 60°C to give the title compound (3.34 g).

¹H-NMR (DMSOd₆) δ 1.36 (3H, d, J= 7.1 Hz), 4.36 (2H, q, J= 7.1 Hz), 7.40 (IH, s), 8.09 (2H, d, 5 J= 8.7 Hz), 8.26 (2H, d, J= 8.7 Hz), 8.67 (IH, s), 12.77 (IH, br s).

(v) Production of 4-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-6-yl]benzoic acid hydrochloride

A mixture of ethyl 4-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride

(1.297 g), 3-me%14-[(6-me%lpyridin-3-yl)oxy]aniline (1.00 g), dϋsopropylethylamine (0.834 g) i o and l-methyl-2-pyrrolidinone (12.5 mL) was stirred at 140°C for 3 hrs, poured into water (100 mL)-ethyl acetate (150 mL) and the precipitated solid was collected by filtration. The solid was washed with ethyl acetate and dried under reduced pressure at 60°C. The obtained solid was suspended in methanol (40 mL), and IN aqueous sodium hydroxide solution (20 mL) was added.

After stirring at room temperature for 12 hrs, the solvent was evaporated under reduced pressure, 15 and the residue was adjusted to pH 2 with IN hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60⁰C to give the title compound (1.08 g).

¹H-NMR (DMSOd₆) δ 2.21 (3H, s), 2.44 (3H, s), 6.98 (IH, d, J= 9.0 Hz), 7.15 (IH, s), 7.17-7.25

(2H, m), 7.76 (IH, d, J= 8.7 Hz), 7.85 (IH, s), 8.01-8.17 (5H, m), 8.48 (IH, s), 9.99 (IH, br s), 12.47 0 (IH, br s).

Synthesis Example 76

Production of 4-[4-({3-cHoro^-[(3-fluorobenzyl)oxy]phenyl} 6-yl]benzoic acid hydrochloride

A mixture of ethyl 4-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-6-yl)benzoate hydrochloride 5 (517 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (462 mg) and l-methyl-2-pyrrolidinone (8 mL) was stirred at 140⁰C for 5 hrs, poured into water (40 mL), and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The precipitated solid was collected by filtration, washed with water and suspended in methanol (15 mL). After stirring at room temperature for 30 min, the solid was collected by filtration and dried under reduced pressure at 60⁰C. The obtained solid was i o suspended in ethanol (10 mL) and IN aqueous sodium hydroxide solution (1.5 mL) was added. After stirring at room temperature for 6.5 hrs, and at 60⁰C for 3.5 hrs, the mixture was cooled to room temperature. IN Hydrochloric acid (155 mL) was added, and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure at 60⁰C to give the title compound (498 mg). is ¹H-NMR (DMSOd₆) δ 5.24 (2H, s), 7.12-7.35 (5H, m), 7.48 (IH, m), 7.70 (IH₅ d, J= 8.7 Hz), 8.01-8.12 (4H, m), 8.27 (IH, s), 8.37 (IH, s), 9.65 (IH₅ br s), 12.15 (IH, br s). Synthesis Example 77

Production of 6-(2-fι^l)-5-me1iLyl-N-{3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrirrύdrn-4-amine

(i) Production of 4-cUoro-6-(2-furyl)-5-me1iiyl-5H-pyrrolo[3,2-d]pyrirnidine 5 To a solution of 4-cMoro-6-(2-fiiryl)-5H-pyπolo[3,2-d]pyrirnidine (220 mg) in N₅N- dimethylformatnide (2.5 mL) were added potassium carbonate (139 mg) and methyl iodide (0.25 mL) and the mixture was stirred at room temperature for 8 hrs. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mLx3). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was i o subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4: 1 -> 0: 1) to give the title compound (94 mg).

¹H-NMR (CDCl₃) δ 4.29 (3H, s), 6.62 (IH, dd, J= 3.6, 1.8 Hz), 6.86 (IH, d, J= 3.6 Hz), 6.94 (IH, s), 7.67 (IH, d, J= 1.8 Hz), 8.68 (IH, s). (ii) Production of 6-(2-ftuyl)-5-me1hyl-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H-

15 pyrrolo[3,2-d]pyrimidin-4-amine

A mixture of 4-chloro-6-(2-iuiyl)-5-me1hyl-5H-pviτolo[3,2-d]pyrirnidrne (92 mg), 3- methyl-4-[(6-me1hylpvridin-3-yl)oxy]aniline (102 mg) and l-methyl-2-pyrrolidinone (2.5 mL) was stirred at 140°C for 3.5 hrs, poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (25 mLx2), and the 0 organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=l :1 — > 0:1). The object fraction was concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60⁰C to give the title compound (105 mg). 1H-NMR (DMSO-dβ) δ 2.17 (3H, s), 2.43 (3H, s), 4.12 (3H, s), 6.74 (IH, dd, J= 3.6, 1.2 Hz), 6.76 (IH, s), 6.93 (IH, d, J= 8.7 Hz), 7.05 (IH, d, J= 3.6 Hz), 7.17 (IH, dd, J= 8.7, 2.4 Hz), 7.23 (IH, d, J= 8.7 Hz), 7.46 (IH, dd, J= 8.7, 3.0 Hz), 7.52 (IH, d, J= 2.4 Hz), 7.94 (IH, d, J= 1.2 Hz), 8.16 (IH, d, J= 3.0 Hz), 8.27 (IH, s), 8.71 (IH, br s). Synthesis Example 78

Production of 5-(2-ethoxyemyl)-6-(2-fluyl)-N-{3-methyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}-

5H-pyrrolo[3 ,2-d]pyrimidin-4-arnine

(i) Production of 4-cMoro-5-(2-ethoxyethyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine

To a solution of 4-cWoro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in N₅N- dimethylformamide (1.2 mL) was added cesium carbonate (489 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. 2-Bromoethyl ethyl ether (0.169 mL) was added and the mixture was stirred at room temperature for 2 days. Cesium carbonate (326 mg) and 2- bromoethyl ethyl ether (0.113 mL) were added and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:l -» 1 :4) to give the title compound (76 mg).

¹H-NMR (CDCl₃) δ 1.09 (3H, t, J= 6.9 Hz), 3.42 (2H, q, J= 6.9 Hz), 3.82 (2H, t, J= 6.3 Hz)₃4.92 (2H, t, J= 6.3 Hz), 6.60 (IH, dd, J= 3.6, 2.1 Hz), 6.94 (IH, s), 6.98 (IH, d, J= 3.6 Hz), 7.64 (IH, d, 5 J= 2.1 Hz), 8.68 (lH, s).

(ii) Production of 5-(2-ethoxye%l)-6-(2-furyl)-N-{3-methyl-4-[(6-metliylpyridin-3- yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrirrddin-4-arnine

A mixture of 4-cMoro-5-(2-ethoxye1hyl)-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (76 mg), 3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]aniline (67 mg) and l-methyl-2-pyrrolidinone (1.5 mL) was i o stirred at 140⁰C for 2 hrs, poured into water (8 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (20 mLx2) and the organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=l :1 — > 0:1). The object fraction was concentrated under reduced pressure.

15 Diisopropyl ether-hexane was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60⁰C to give the title compound (78 mg). 1H-NMR (DMSO-de) δ 1.08 (3H, t, J= 6.9 Hz), 2.18 (3H, s), 2.43 (3H, s), 3.52 (2H, q, J= 6.9 Hz), 3.95 (2H, t, J= 4.4 Hz), 4.68 (2H, brt, J= 4.4 Hz), 6.73 (IH, dd, J- 3.6, 1.8 Hz), 6.84 (IH, s), 6.96 (IH, d, J= 8.1 Hz), 7.01 (IH, d, J= 3.6 Hz), 7.16 (IH, dd, J= 8.4, 2.7 Hz), 7.22 (IH, d, J= 8.4 Hz), 0 7.50-7.55 (2H, m), 7.93 (IH, d, J= 1.8,Hz), 8.15 (IH, d, J= 2.7 Hz), 8.31 (IH, s), 9.15 (IH, br s). Synthesis Example 79

Production of {4-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}aniino)-5H-pyrrolo[3,2- d]pyritnidin-6-yl]phenyl}methanol

To a suspension of 4-[4-({3-me&yl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- 5 pyrrolo [3 ,2-d]pyrimidin-6-yl]benzoic acid (122 mg) in tetrahydrofuran (10 mL) was added triethylamine (30.5 mg) and, after stirring at room temperature for 10 min, l,r-carbonyldiimidazole (49 mg) was added, and the mixture was stirred at room temperature for 13 hrs. Under ice-cooling, sodium borohydride (28 mg) was added, and methanol (2.5 mL) was further added. After stirring under ice-cooling for 2 hrs, water (1.5 mL) was added, and tetrahydrofuran and methanol were i o evaporated under reduced pressure. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL)-tetrahydrofuran (15 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (15 mL)-tetrahydrofuran (5 mL). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, ethyl is acetate:methanol=99:l — » 9:1). The object fraction was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to give the title compound (65 mg). 1H-NMR (DMSOd₆) δ 2.21 (3H, s), 2.43 (3H₅ s), 4.57 (2H, d, J= 4.8 Hz), 5.32 (IH, brt, J= 4.8 Hz), 6.96 (IH, s), 6.99 (IH, d, J= 8.4 Hz), 7.18 (IH, dd, J= 8.7, 2.7 Hz), 7.23 (IH, d, J= 8.7 Hz), 7.50 (2H, d, J= 7.8 Hz), 7.74 (IH, dd, J= 8.4, 2.7 Hz), 7.81-7.85 (3H, m), 8.16 (IH, d, J= 2.7 Hz), 8.34 (IH, s), 0 9.09 (IH₅ br s), 11.56 (IH, br s). Synthesis Example 80

Production of N-{3-methyl-4-[(6-mefhylpyridin-3-yl)oxy]phenyl}-6-[4-({[2- (metiiylsulfonyl)ethyl]amino}methyl^^^

5 A mixture of {4-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrirnidin-6-yl]phenyl}methanol (96 mg), manganese dioxide (1.0 g) and N₅N- dimethylformamide (5 mL) was stirred at room temperature for 12 hrs. After celite filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» 9:1). A mixture of the obtained solid, i o methylsulfonylethylamine hydrochloride (27.5 mg), N,N-dirnethylformamide (2 mL) and acetic acid (0.02 mL) was stirred at room temperature for 1 hr, and sodium triacetoxyborohydride (36.6 mg) was added. After stirring at room temperature for 4.5 hrs, saturated aqueous sodium hydrogen carbonate (10 mL) was added, and the mixture was extracted with ethyl acetate (25 mL><2). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under

15 reduced pressure. The residue was subj ected to silica gel column chromatography (ethyl acetate:methanol=10:0 -> 9: 1). The object fraction was concentrated under reduced pressure. Chloroform - diisopropyl ether was added to the residue, and the solid was collected by filtration and dried under reduced pressure at 60⁰C to give the title compound (28 mg). 1H-NMR (DMSOd₆) δ 2.21 (3H, s), 2.44 (3H, s), 2.94 (2H, t, J= 6.6 Hz), 3.00 (3H, s), 3.29 (2H, t, 0 J= 6.6 Hz), 3.78 (2H, s), 6.97 (IH, s), 7.00 (IH, d, J= 8.7 Hz), 7.19 (IH, dd, J= 8.4, 2.7 Hz), 7.24 (IH, d, J== 8.4 Hz), 7.51 (2H, d, J= 8.4 Hz), 7.77 (IH, dd, J= 8.7, 2.4 Hz), 7.83-7.87 (3H, m), 8.18 (IH, d, J= 2.4 Hz), 8.34 (IH, s), 9.23 (IH, br s), 11.73 (IH, br s).

Synthesis Example 81

5 Production of 6-(aminome1hyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (i) Production of N4-{3-cUoro-4-[(3-fluoroberizyl)oxy]phenyl}-6-iodopyriirddine-4,5-diamine

A solution of 5-airiino-4,6-diiodopyrirnidine (3.83 g) and 3-chloro-4-[(3- fluorobenzyl)oxy]aniline (2.78 g) in l-methyl-2-pyrrolidone (30 mL) was stirred at 70⁰C for 14 hrs. i o Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=l :4 -> 2:3 -> 1 :1) to give the title compound (4.21 g) as brown powder crystals. is ¹H-NMR (CDCl₃) δ: 3.47 (2H, br s), 5.13 (2H, s), 6.73 (IH, br s), 6.92 (IH, d, J= 9.0 Hz), 6.96-7.04 (IH, m), 7.15-7.25 (2H, m), 7.31-7.38 (2H, m), 7.64 (IH, d, J= 2.7 Hz), 8.04 (IH, s). (ϋ) Production of tert-butyl 3-[5-amino-6-({3-chloro-4-[(3- fiuorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]prop-2-ynylcarbamate

To a solution of N4-{3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrirnidine-4,5- 0 diamine (0.84 g) and tert-butyl prop-2-ynylcarbamae (0.36 g) in acetonitiile-triethylamine (20 mL- 15 mL) were added bis(triphenylphosphine)palladium(II) dichloride (62.5 mg) and copper(T) iodide (20.3 mg) at room temperature, and the mixture was stirred at room temperature under an argon atmosphere for 6 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (eluent, ethyl acetate:hexane=l : 1 — » ethyl acetate) to give the title compound (766.5 mg) as a brown solid.

¹H-NMR (DMSOd₆) δ: 1.42 (9H, s), 4.06 (2H, d, J= 5.4 Hz), 5.22 (2H, s), 5.45 (2H, br s), 7.13- 7.23 (2H, m), 7.26-7.34 (2H, m), 7.42-7.51 (2H, m), 7.54-7.60 (IH, m), 7.95 (2H, s), 8.54 (IH, s). (ϋi) Production of tert-butyl [4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirnidin-6-yl]methylcarbamate A mixture of tert-butyl (3-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}arrirno)pyiiιmα1n-4-yl]prop-2-ynylcarbamate (720 mg) and copper(T) iodide (55.2 mg) inN,N-dimethylformamide (7.0 mL) was stirred at 8O⁰C for 12 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate — > methanol:ethyl acetate=l :9) to give the title compound (604 mg) as pale-yellow powder crystals.

¹H-NMR (DMSOd₆) δ: 1.42 (9H, s), 4.33 (2H, d, J= 5.7 Hz), 5.22 (2H, s), 6.29 (IH, s), 7.14-7.35 (4H, m), 7.41-7.60 (3H, m), 8.16 (IH, d, J= 2.7 Hz), 8.30 (IH, s), 9.29 (IH, s), 10.96 (IH, br s). (iv) Production of 6-(arninomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrirnidin-4-amine dihydrochloride To a solution of tert-butyl [4-({3-cMoro-4-[(3-fluoroberizyl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidin-6-yl]methylcarbamate (500 mg) in tetrahydrofuran (12 mL) was added 2N hydrochloric acid (6.0 mL) at room temperature. The mixture was stirred at 60°C for 2 hrs, ethanol was added to the reaction system and the mixture was concentrated under reduced pressure. The resultant crystals were collected by filtration and washed with dϋsopropyl ether to give the title compound (481.4 mg) as pale-yellow powder crystals.

¹H-NMR (DMSO-de) δ: 4.28-4.39 (2H, m), 5.28 (2H, s), 6.89 (IH, s), 7.15-7.25 (IH, m), 7.29-7.40 (3H, m), 7.45-7.54 (IH, m), 7.73-7.80 (IH, m), 8.15 (IH, s), 8.48-8.65 (3H, m), 8.82 (IH, s). Synthesis Example 82

Production of (2E)-N-{[4-({3-cUoro-4-[(3-fluoiObenzyl)oxy]phenyl}arrrino)-5H-pyrrolo[3,2- d]pyrirnidin-6-yl]methyl}-4-(dime1hylarnino)but-2-enarnide

A solution of 6-(aminomethyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-arnine dihydrochloride (150 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (105 mg), l-emyl-3-(3-dimethylamrnopropyl)carbodiimide hydrochloride (244 mg), 1-hydroxybenzotriazole monohydrate (196 mg) andtriethylamine (0.30 mL) in N₉N- dimethylformamide (5 mL) was stirred at room temperature for 2 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, methanol:ethyl acetate=l :9 -> 1 :4) to give the title compound (104.2 mg) as pale-brown powder crystals. 1H-NMR (DMSOd₆) δ: 2.14 (6H, s), 3.00 (2H, d, J= 6.1 Hz), 4.54 (2H, d, J= 5.7 Hz)₅ 5.21 (2H, s), 6.11 (IH, d, J= 15.3 Hz), 6.35 (IH, s), 6.66 (IH, dt, J= 15.3, 6.1 Hz), 7.12-7.34 (4H, m), 7.41-7.49 (IH, m), 7.53-7.60 (IH, m), 8.14 (IH, d, J= 2.4 Hz), 8.29 (IH, s), 8.69 (IH, t, J= 5.7 Hz), 9.34 (IH, br s), 10.99 (IH, br s).

Synthesis Example 83

Production of 6-(3-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidm-4-amine

(i) Production of 6-[(3-arninophenyl)ethynyl]-N4-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}pyrirnio%e-4,5-diarnine i o The title compound (1.35 g) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ii) using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-

64odopyrimidine-4,5-diamine (1.90 g), 3-aminophenylacetylene (0.41 mL), bis(triphenylphosphine)paUadium(Η) dichloride (102 mg), coppeπT) iodide (27 mg), acetonitrile (24 mL) and triethylamine (18 mL). is ¹H-NMR (CDCl₃) δ: 3.65-3.78 (4H, m), 5.15 (2H, s), 6.59 (IH, s), 6.73 (IH, d, J= 8.1 Hz), 6.90-

7.06 (4H, m), 7.14-7.41 (5H, m), 7.68 (IH, d, J= 2.7 Hz), 8.35 (IH, s).

(ii) Production of 6-(3-arninophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrirnidin-4-arnine

The title compound (673 mg) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (iϋ) using 6-[(3-aminophenyl)ethynyl]-N4-{3-chloro-4- [(3-fluorobenzyl)oxy]phenyl}pyrimidine-4,5-diamine (1.30 g), coppeπl) iodide (54 mg) andN,N- dimethylformamide (7.0 mL).

¹H-NMR (DMSO-de) δ: 5.23 (2H, s), 5.31 (2H, s), 6.58-6.65 (IH, m), 6.75 (IH, s), 6.94-7.01 (2H, 5 m), 7.13-7.34 (5H_S m), 7.43-7.50 (IH, m), 7.57 (IH, dd, J= 8.9, 2.6 Hz), 8.19 (IH, d, J= 2.1 Hz), 8.32 (IH, s), 9.13 (IH, s), 11.40 (IH, s). Synthesis Example 84

Production of N-{3-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- i o d]pyrJmidin-6-yl]phenyl} -2-methoxyacetamide

The title compound (42.9 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 82 using 6-(3-aminophenyl)-N-{3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}-5H-pyiτolo[3,2-d]pyiimidb4-amine (80 mg), methoxyacetic acid (31 mg), l-e1hyl-3-(3-dimethylaminopropyl)c-u:bodiimide hydrochloride (67 mg), 1- i 5 hydroxybenzotriazole monohydrate (54 mg), triethylamine (0.1 mL) and N,N-dimethylformamide (5 mL).

¹H-NMR (DMSO-de) δ: 3.42 (3H, s), 4.06 (2H, s), 5.24 (2H, s), 6.87 (IH, s), 7.13-7.36 (4H, m), 7.44-7.69 (5H, m), 8.19-8.26 (2H, m), 8.35 (IH, s), 9.25 (IH, s), 9.95 (IH, s), 11.56 (IH, s). Synthesis Example 85

Production of 6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine

(i) Production of 6-[(4-amrnophenyl)ethynyl]-N4-{3-chloro-4-[(3- 5 fluorobenzyl)oxy]phenyl}pyrirrήdMe-4,5-diarnine

The title compound (1.12 g) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 81 (ϋ) using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyiimidine-4,5-diamine (1.50 g), 4-aminophenylacetylene (411 mg), bis(triphenylphosphine)palladium(π) dichloride (112 mg), copper(T) iodide (36.5 mg), acetonitrile i o (24 mL) and triethylamine (18 mL).

¹H-NMR (CDCl₃) δ: 3.68 (2H, br s), 3.94 (2H, br s), 5.14 (2H, s), 6.58 (IH, br s), 6.65 (2H₃ d, J=

7.8 Hz), 6.95 (IH, d, J= 9.0 Hz), 6.96-7.06 (IH, m), 7.19-7.43 (6H, m), 7.68 (IH, d, J= 2.7 Hz), 8.34

(IH, s).

(ii) Production of 6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2- is d]pyrimidin-4-amine

The title compound (768.6 mg) was obtained as yellow powder crystals by the reaction in the same manner as in Synthesis Example 81 (iϋ) using 6-[(4-aminophenyl)ethynyl]-N4-{3-chloro-

4-[(3-fluorobenzyl)oxy]phenyl}pyrirrjidine-4,5-diamine (1.11 g), copper(T) iodide (46 mg) and

N,N-drmethylformamide (6.0 mL). ¹H-NMR (DMSOd₆) δ: 5.22 (2H₃ s), 5.53 (2H, s), 6.65-6.70 (3H, m), 7.12-7.35 (4H, m), 7.42-7.61 (4H, m), 8.17 (IH, d, J= 2.7 Hz), 8.28 (IH, s), 8.99 (IH, s), 11.21 (IH, br s). Synthesis Example 86

5 Production of N-{4-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyiτolo[3,2- d]pyrirnidin-6-yl]phenyl}-2-mefhoxyacetamide

A solution of 6-(4-aminophenyl)-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-atnine (100 mg), methoxyacetic acid (29.4 mg), l-ethyl-3-(3- dimethylaminopropyl)carbocliimide hydrochloride (94 mg), 1-hydroxybenzotriazole monohydrate i o (75 mg) and triethylamine (0.23 mL) in N,N-dimefhylformamide (5 mL) was stirred at room temperature for 20 hrs. Methoxyacetic acid (29.4 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (94 mg) and 1-hydroxybenzotriazole monohydrate (75 mg) were added to the reaction system, and the mixture was further stirred for 24 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The

15 organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate — > methanol:ethyl acetate=14:85) to give the title compound (63.5 mg) as pale-brown powder crystals. 1H-NMR (DMSOd₆) δ: 3.40 (3H, s), 4.04 (2H, s), 5.23 (2H, s), 6.90 (IH, s), 7.12-7.21 (IH, m), 7.23-7.35 (3H, s), 7.43-7.49 (IH, m), 7.52-7.60 (IH, m), 7.78-7.87 (4H, m), 8.19 (IH, d, J= 1.8 Hz), 8.33 (IH, s), 9.07 (IH, s), 9.97 (IH, s), 11.45 (IH, s). Synthesis Example 87

Production of (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-6-yl]prop-2-en- 1 -ol

The title compound (188.2 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 81 (ϋ) using N4-{3-chlόro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrirrύdine-4,5-diamine (300 mg), 2-penten-4-yn-l-ol (58 mg), bis(triphenylphosphine)palladium(IT) dichloiϊde (22.5 mg), copper(I) iodide (7.3 mg), acetonitrile

(6.0 mL) and triethylamine (4.5 mL).

¹H-NMR (DMSO-Cl₆) δ: 4.06-4.15 (2H, m), 5.06 (IH, t, J= 5.4 Hz), 5.21 (2H, s), 5.45 (2H, br s), 5.98-6.07 (IH, m), 6.46-6.57 (IH, m), 7.12-7.34 (4H₅ m), 7.39-7.59 (2H, m), 7.92-7.99 (2H, m),

8.55 (IH, br s).

(ϋ) Production of (2E)-3 ~[4-({3 -chloro-4- [(3 -fluorobenzyl)oxy]phenyl} amino)-5H-pyrrolo [3 ,2- d]pyrimidin-6-yl]prop-2-en- 1 -ol

The title compound (98 mg) was obtained as pale-yellow powder crystals by the reaction in the same manner as in Synthesis Example 81 (iii) using (2E)-5-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amino)pyrimidin-4-yl]pent-2-en-4-yn-l-ol (170 mg), copper(T) iodide (7.6 mg) andN,N-dimethylforniamide (1.5 mL).

¹H-NMR (DMSOd₆) δ: 4.16-4.24 (2H, m), 5.02-5.09 (IH, m), 5.22 (2H, s), 6.40-6.52 (2H, m), 6.66 (IH, d, J= 15.9 Hz), 7.13-7.34 (4H₅ m)₅7.41-7.50 (IH, m), 7.52-7.60 (IH₅ m)₅ 8.17 (IH, d, J= 2.7 Hz)₅ 8.29 (IH, s), 9.13 (IH₅ br s)₅ 11.38 (IH₅ br s). Synthesis Example 88

Production of 3-[4-({3-cMoro^-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrirmdin- 6-yl]propan-l-ol

(i) Production of 5-[5-amino-6-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrirrddin-4- yl]pent-4-yn-l-ol

To a solution of N4-{3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodopyrimidine-4_!5- diamine (300 mg) and 4-pentyn-l-ol (65 mg) in acetonitrile-triethylamine (6.0 mL-4.5 mL) were added bis(triphenylphosphine)palladium(II) dichloride (22.5 mg) and copper(T) iodide (7.3 mg) at room temperature, and the mixture was stirred at room temperature under an argon atmosphere for 24 hrs. 4-Pentyn-l-ol (65 mg), bis(triphenylphosphine)palladium(H) dichloride (22.5 mg) and copper(T) iodide (7.3 mg) were added to the reaction system and the mixture was stirred at 60°C for 2 hrs. After concentration under reduced pressure, the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate -> methanol:ethyl acetate=l : 19) to give the title compound (157.2 mg) as a yellow solid.

¹H-NMR (DMSOd₆) δ: 1.66-1.79 (2H, m), 2.43-2.58 (2H, m), 3.53 (2H, q, J= 5.4 Hz), 4.61 (IH, t,

J= 5.1 Hz), 5.20 (2H, s), 5.31 (2H, s), 7.11-7.21 (2H, m), 7.25-7.33 (2H, m), 7.39-7.50 (IH, m), 7.55 5 (IH, dd, J= 9.0, 2.1 Hz), 7.92-7.94 (2H, m), 8.50 (IH, s).

(ϋ) Production of 3-[4-({3-cWoro4-[(3-fluorobenzyl)oxy]phenyl}atnino)-5H-pyrrolo[3,2- d]pyrimidin-6-yl]propan-l -ol

A mixture of 5-[5-arrύno-6-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}ammo)pyriimdin-4- yl]pent-4-yn-l-ol (140 mg) and copperQ iodide (19 mg) inN,N-dimethylformamide (2.0 mL) was i o stirred at 80⁰C for 5 hrs. After concentration under reduced pressure, and the residue was separated and purified by column chromatography (basic silica gel, eluent, ethyl acetate — » methanol:ethyl acetate=15:85) to give the title compound (95.2 mg) as pale-brown powder crystals.

¹H-NMR (DMSOd₆) δ: 1.79-1.91 (2H, m), 2.84 (2H, t, J= 7.8 Hz), 3.44-3.52 (2H, m), 4.62-4.68

(IH, m), 5.22 (2H, s), 6.24 (IH, s), 7.13-7.35 (4H, m), 7.43-7.59 (2H, m), 8.17 (IH, d, J= 2.7 Hz), is 8.29 (IH, s), 9.01 (IH, br s), 10.94-11.05 (IH, m).

Synthesis Example 89

Production of 4-[4-({3-cHoro-4-[(3~fluoroberizyl)oxy]phenyl}amM^ 6-yl]butan-l-ol (i) Production of 6-[5-atnino-6-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)pyrimidin-4- yl]hex-5-yn-l-ol

The title compound (242 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 81 (H) using N4-{3-chloro-4-[(3-fLuorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-diamine (300 mg), 5-hexyn-l-ol (94.2 mg), bis(triphenylphosphine)palladium(π) dichloride (22.5 mg), copper® iodide (7.3 mg), acetonitrile

(6.0 mL) and triethylamine (4.5 mL).

¹H-NMR (DMSOd₆) δ: 1.51-1.69 (4H, m), 2.39-2.58 (2H, m), 3.41-3.47 (2H, m), 4.46 (IH, t, J=

4.8 Hz), 5.20 (2H, s), 5.28 (2H, br s), 7.12-7.22 (2H, m), 7.25-7.33 (2H, m), 7.41-7.49 (IH₅ m), 7.55 (IH, dd, J= 8.6, 2.9 Hz), 7.89-7.96 (2H, m), 8.50 (IH, s).

(ii) Production of 4-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-6-yl]butan-l -ol

The title compound (109 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ϋi) using 6-[5-amino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}ammo)pyrimidin-4-yl]hex-5-yn-l-ol (220 mg), copperQ iodide (9.5 mg) andN,N-dimethylformamide (4.0 mL).

¹H-NMRpMSOd₆) δ: 1.44-1.56 (2H, m), 1.67-1.81 (2H, m), 2.80 (2H, t, J= 7.8 Hz), 3.45 (2H, t,

J= 6.0 Hz), 4.40-4.50 (IH, m), 5.21 (2H_S s), 6.22 (IH, s), 7.12-7.32 (4H, m), 7.42-7.55 (2H, m), 8.15

(IH, d, J= 2.7 Hz), 8.27 (IH, s), 8.98 (IH, s), 10.93 (IH, br s). Synthesis Example 90

Production of 6-[(lE)-3-aminoprop-l-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-anώie

(i) Production of teat-butyl (2E)-5-[5-atnino-6-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}arrύno)pyrirrύdin-4-yl]pent-2-en-4-ynylcarbamate

The title compound (373.8 mg) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 81 (ii) using N4-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6- iodopyrimidine-4,5-diamine (600 mg), tert-butyl pent-2-en-4-ynylcarbamate (0.26 g), bis(triphenylphosphine)palladium(II) dichloride (44.6 mg), copper(T) iodide (14.5 mg), acetonitrile (12 mL) and triethylamine (9 mL).

¹H-NMR (DMSO-de) δ: 1.40 (9H, s), 3.66-3.75 (2H, m), 5.21 (2H, s), 5.49 (2H₅ br s), 5.91 (IH₅ d,

J= 10.2 Hz), 6.30-6.42 (IH, m), 7.12-7.25 (3H, m), 7.27-7.36 (2H, m), 7.42-7.51 (IH, m), 7.54-7.62

(IH, m), 7.93-7.99 (2H, m), 8.58 (IH, s).

(ii) Production of tert-butyl (2E)-3-[4-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidin-6-yl]prop-2-enylcarbamate

The title compound (189 mg) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (in) using tert-butyl (2E)-5-[5-amino-6-({3-chloro-

4-[(3-fluorobenzyl)oxy]phenyl}arrrmo)pyri^ copperQ iodide (12.7 mg) andN,N-drmethylformamide (2.0 mL). ¹H-NMR(DMSO-Cl₆) δ: 1.41 (9H, s), 3.73-3.85 (2H, m), 5.23 (2H, s), 6.22-6.36 (IH, m), 6.48-6.62 (2H, m), 7.14-7.38 (5H, m), 7.42-7.50 (IH, m), 7.52-7.62 (IH, m), 8.18 (IH, s), 8.30 (IH, s), 9.06 (lH, br s), 11.29 (lH, br s).

(iii) Production of 6-[(lE)-3-arainoprop-l-enyl]-N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5H- 5 pyrrolo[3,2-d]pyrirnidin-4-aπώie

To a solution of tert-butyl (2E)-3-[4-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-6-yl]prop-2-enylcarbamate (150 mg) intetrahydrofuran (6.0 mL) was added 2N hydrochloric acid (3.0 mL) at room temperature and the mixture was stirred at 60°C for 2 hrs. IN Aqueous sodium hydroxide solution was added to alkalize the reaction system. After i o extraction with chloroform, the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resultant crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (104 mg) as pale-brown powder crystals. 1H-NMR PMSOd₆) δ: 3.42 (2H, d, J= 4.2 Hz), 5.22 (2H, s), 6.41-6.50 (2H, m), 6.62 (IH₅ d, J= 15.9 Hz), 7.12-7.35 (4H, m), 7.42-7.50 (IH, m), 7.57-7.60 (IH, m), 8.18 (IH, d, J= 2.1 Hz), 8.28 is (IH, s), 9.20 (IH, br s), 11.39 (IH, br s). Synthesis Example 91

Production of N-{(2E)-3-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3 ,2- d]pyrimidin-6-yl]prop-2-enyl}-2-methoxyacetamide The title compound (23.2 nig) was obtained as pale-brown powder crystals by the reaction in the same manner as in Synthesis Example 82 using 6-[(lE)-3-aminoprop-l-enyl]-N-{3-chloro-4- [(3-fluorobenzyl)oxy]phenyl}-5H-pyπ:olo[3,2-d]pyrirrddin^-amine (30 mg), methoxyacetic acid (14 mg), l-ethyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (55 mg), 1- 5 hydroxybenzotriazole monohydrate (44 mg), triethylamine (0.1 mL) and N,N-dimethyrformamide (5 mL).

¹H-NMR (DMSOd₆) δ: 3.34 (3H, s), 3.87 (2H, s), 3.95 (2H, t, J= 5.4 Hz), 5.21 (2H, s), 6.35 (IH, dt, J= 16.2, 5.7 Hz), 6.47 (IH, s), 6.56 (IH, d, J= 16.2 Hz), 7.12-7.32 (4H₅ m), 7.41-7.50 (IH, m), 7.62 (IH, dd, J= 9.0. 2.7 Hz), 8.16-8.25 (2H, m), 8.28 (IH, s), 9.37-9.52 (IH, m), 11.67-11.84 (IH, m). i o Synthesis Example 92

Production of (2E)-N-{(2E)-3-[4-({3-cWoro-4-[(3-fluorober^l)oxy]phenyl}amino)-5H- pyrrolo [3 ,2-d]pyrimidin-6-yl]prop-2-enyl} -4-(dimethylamino)but-2-enamide

The title compound (25.6 mg) was obtained as pale-yellow powder crystals by the reactions in the same manner as in Synthesis Example 82 using 6-[(lE)-3-aminoprop-l-enyl]-N-{3-chloro-4- [(3-fluorobenzyl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrirrudin-4-amine (40 mg), (2E)-4- (dimethylamino)but-2-enoic acid hydrochloride (31 mg), l-ethyl-3-(3- dime1hylarninopropyl)carbodiimide hydrochloride (72 mg), 1 -hydroxybenzotriazole monohydrate (58 mg), triethylamine (0.13 mL) andN,N-dimethylformamide (5 mL). ¹H-NMR. (DMSOd₆) δ: 2.15 (6H, s), 3.00 (2H, d, J= 6.3 Hz), 3.97-4.06 (2H, m), 5.23 (2H₃ s), 6.10 (IH, d, J= 15.3 Hz), 6.27-6.40 (IH, m), 6.51 (IH, s), 6.55-6.68 (2H, m), 7.14-7.36 (4H, m), 7.43- 7.60 (2H, m), 8.17 (IH, d, J= 2.7 Hz), 8.31 (IH, s), 8.41-8.45 (IH, m), 9.01 (IH, s), 11.22 (IH, s). Synthesis Example 93

Production of 2-{[2-cUoro-4-(5H-pyπ"olo[3,2-d]pyrπmdin-4-ylamino)phenoxy]methyl}benzoώ

The title compound (272 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ii) using 4-cUoro-5H-pyrrolo[3,2-d]pyrimidrne (200 mg) and 2-[(4-amino-2- chlorophenoxy)methyl]benzonitrile (337 mg). i o ¹H-NMR (DMSOd₆) 5 5.33 (2H, s), 6.49 (IH, s), 7.32 (IH, d, J= 9.0 Hz), 7.57-7.68 (3H, m), 7.78- 7.80 (2H, m), 7.94 (IH, d, J= 8.1 Hz), 8.20 (IH, m), 8.36 (IH, s), 9.32 (IH, br s), 11.1 (IH, br s). Synthesis Example 94

Production of 3-[2-methyl-4-(5H-pyrrolo[3,2-d]pyrirrύdin-4-ylarrrino)phenoxy]benzorύ 5 The title compound (338 mg) was obtained by the reaction in the same manner as in

Synthesis Example 2 (ii) using 4-cWoro-5H-pyrrolo[3,2-d]pyrimidine (200 mg) and 3-(4-amino-2- methylphenoxy)benzonitrile (292 mg).

¹H-NMR (DMSO-Cl₆) δ 2.16 (3H, s), 6.49 (IH, s), 7.06 (IH, d, J= 9.3 Hz), 7.21 (IH, m), 7.35 (IH, s), 7.51-7.59 (2H, m), 7.69 (IH, m), 7.80-7.83 (2H, m), 8.35 (IH, s), 9.26 (IH, s), 11.1 (IH, br s).

Synthesis Example 95

Production of 3 - [2-chloro-4-(5H-pyrrolo [3 ,2-d]pyriinidin-4-ylamino)phenoxy]benzonitrile

The title compound (230 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ii) using 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (150 mg) and 3-(4-amino-2- chlorophenoxy)benzonitiile (219 mg). i o ¹H-NMR (DMSOd₆) δ 6.53 (IH, s), 7.26 (IH, m), 7.32 (IH, d, J= 8.7 Hz), 7.45 (IH, s), 7.58 (2H, d, J= 5.7 Hz), 7.70-7.73 (2H, m), 8.41 (2H, s), 9.50 (IH, s), 11.1 (IH, br s). Synthesis Example 96

Production of 2-{ [2-methyl-4-(5H-pyrrolo[3,2-d]pyrimidin-4-5 ylatnino)phenoxy]methyl}benzonitrile

The title compound (250 mg) was obtained by the reaction in the same manner as in Synthesis Example 2 (ϋ) using 4-cMoro-5H-pyrrolo[3,2-d]pyrirrύdine (200 mg) and 2-[(4-arnino-2- methylphenoxy)methyl]benzonitrile (310 mg).

¹H-NMR (DMSOd₆) δ 2.24 (3H, s), 5.26 (2H, s), 6.46 (IH, t, J= 1.5 Hz), 7.08 (IH, d, J= 9.0 Hz), 7.58-7.68 (4H, m), 7.78 (2H, d, J= 4.2 Hz), 7.94 (IH, d, J= 7.5 Hz), 8.29 (IH, s), 9.02 (IH, br s), 5 ll.l (lH, br s).

Synthesis Example 97

Production of N- {3 -chloro-4-[(3-fluorobenzyl)oxy]phenyl} - 1 H-pyrazolo[4,3 -d]pyrimidin-7-amine A mixture of 7-(methylthio)-lH-pyra2»lo[4,3-d]pyrimidine (known compound from i o literature: J. Am. Chem. Soα, 1956, 78, 2418) (150 mg), 3-cMoro-4-[(3-fluorobenzyl)oxy]aniline (227 mg) and pyridine hydrochloride (156 mg) in l-methyl-2-pyrrolidone (3 mL) was stirred at 12O⁰C for 10 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel column is chromatography (hexane/ethyl acetate=l/3 — > 1/10) to give the title compound (220 mg, yield 61%) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 5.15 (2H, s), 6.96 (IH, d, J= 8.7 Hz), 7.03 (IH, m), 7.20-7.26 (2H, m), 7.36 (IH, dt, J= 5.7, 8.4 Hz), 7.71 (IH, dd, J= 2.7, 9.0 Hz), 7.81 (IH, d, J= 2.7 Hz), 8.14 (IH, s), 8.57 (IH, s). Synthesis Example 98

Production of N- {3 -methyl-4-[(6-methylpyridin-3 -yl)oxy]phenyl} - 1 H-pyrazolo [4,3 -d]pyrimidin-7~ atnine The title compound (195 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methyltMo)-lH-pyrazolo[4,3-d]pyrimidine (150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (193 mg) and pyridine hydrochloride (156 mg). ¹H-NMR (CDCl₃) δ 2.13 (3H, s), 6.89 (IH, d, J= 8.4 Hz), 7.11 (IH, d, J= 8.1 Hz), 7.15 (IH, dd, J= 2.7, 8.4 Hz), 7.50 (IH, dd, J= 2.7, 9.0 Hz), 7.68 (IH, d, J= 2.7 Hz), 8.14 (IH, s), 8.25 (IH, d, J= 2.7 Hz), 8.58 (IH, s).

Synthesis Example 99

Production of me1hyl 4-{[7-({3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyrazolo[4,3- djpyrimidin- 1 -yl]methyl}benzoate

The title compound (45 mg) was obtained as a brown solid by the reaction in the same manner as in Synthesis Example 97 using methyl 4-{[7-(methyliMo)-lH-pyrazolo[4,3-d]pyrimidin- l~yl]methyl}benzoate (120 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (87 mg) andpyiidine hydrochloride (60 mg).

¹H-NMR (CDCl₃) δ 3.94 (3H, s), 5.11 (2H, s), 5.90 (2H, s), 6.34 (IH, br s), 6.85 (IH, d, J= 8.7 Hz), 6.94 (IH, dd, J= 2.7, 8.7 Hz), 7.01 (IH, m), 7.16-7.22 (2H, m), 7.32 (2H, d₅ J= 8.7 Hz), 7.35 (IH, m), 8.14 (2H, d, J= 8.7 Hz), 8.18 (IH, s), 8.51 (IH, s). Synthesis Example 100

Production of methyl 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoate

The title compound (140 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using methyl 4-{[7-(methylthio)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoate (150 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]anilitie (109 mg) and pyridine hydrochloride (75 mg). 1H-NMR (CDCl₃) δ 3.92 (3H, s), 5.16 (2H, s), 5.62 (2H, s), 6.97 (IH, d, J= 8.8 Hz), 7.02 (IH, m), 7.18-7.42 (4H, m), 7.55-7.68 (2H, m), 8.00-8.08 (4H, m), 8.50 (IH, s).

Synthesis Example 101

Production of 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl} amino)- lH-pyrazolo[4,3- d]pyrirnidin-l-yl]rnethyl}benzoic acid

To a solution of methyl 4-{[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-lH- 5 pyrazolo[4,3-d]pyrimidin-l-yl]methyl}benzoate (25 mg) in a mixed solvent of tetrahydrofuran/methanol (1:1, 1 mL) was added IN aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hr. After the completion of the reaction, IN aqueous hydrochloric acid solution (0.5 mL) and water (1 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The resultant solid was collected by filtration, i o and washed with diisopropyl ether and dried to give the title compound (16 mg) as pale-yellow crystals.

¹H-NMR (T>MSO-d₆) δ 5.24 (2H, s), 6.10 (2H, s), 7.13-7.31 (5H, m), 7.42-7.47 (2H, m), 7.70 (IH, m), 7.83-7.91 (2H, m), 8.27 (IH, s), 8.35 (IH, s), 8.81 (IH, s), 12.9 (IH, br s). Synthesis Example 102

Production of 4-{[7-({3-cMoro4-[(3-fluoroberizyl)oxy]phenyl}aniino)-2H-pyra2x>lo[4,3- d]pyrimidin-2-yl]methyl}benzoic acid

The title compound (130 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-{[7-({3-chloro-4-[(3- 5 fluorobenzyl)oxy]phenyl}ammo)-2H-pyra^ (150 mg) and IN aqueous sodium hydroxide solution (6 mL).

¹H-NMR (DMSO-de) δ 5.26 (2H, s), 5.85 (2H₅ s), 7.15-7.32 (4H, m), 7.41 (2H, d, J= 8.1 Hz), 7.45 (IH, m), 7.72 (IH, dd, J= 2.4, 8.7 Hz)₅7.94 (2H, d, J- 8.1 Hz)₅ 8.06 (IH, d, J= 2.1 Hz)₅ 8.65 (IH, s), 8.85 (IH₅ S)₅ 11.4 (IH, br s). i o Synthesis Example 103

Production of 4-{[7-({3-me1riyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-lH-pyrazolo[4₅3- d]pyrimidin-l-yl]methyl}benzoic acid

Methyl 4-{[7-({3-methyl-4-[(6-methylpyridrn-3-yl)oxy]phenyl}arnino)-lH-pyrazolo[4₅3- 5 djpyrimidin- 1 -yl]methyl}benzoate was obtained as a mixture with 1 -methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using methyl 4- { [7-(methylthio)- 1 H- pyrazolo[4₅3-d]pyrimidin-l-yl]methyl}benzoate (120 mg), 3-methyl-4-[(6-methylpyridin-3- yl)oxy]aniline (87 mg) and pyridine hydrochloride (60 mg).

The title compound (20 mg) was obtained as yellow crystals by the reaction in the same0 manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (1 mL).

¹H-NMR (DMSOd₆) δ 2.17 (3H, s), 2.43 (3H, s), 6.12 (2H, s), 6.91 (2H, d, J= 8.7 Hz), 7.12-7.24 (4H, m), 7.38-7.47 (2H, m), 7.85 (2H, d, J= 8.1 Hz), 8.16 (IH, d, J= 2.4 Hz), 8.28 (IH, s), 8.35 (IH, s), 8.81 (IH, s). 5 Synthesis Example 104

Production of methyl 4-{[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate

The title compound (160 mg) was obtained as pale-yellow crystals by the reaction in the i o same manner as in Synthesis Example 97 using methyl 4-{[7-(methylthio)-2H-pyrazolo[4,3- d]pyrirnidin-2-yl]methyl}benzoate (150 mg), 3-me1hyl-4-[(6-methylpyridm-3-yl)oxy]aniIine (93 mg) and pyridine hydrochloride (75 mg).

¹H-NMR (CDCl₃) δ 2.27 (3H, s), 2.52 (3H, s), 3.91 (3H, s), 5.60 (2H, s), 6.90 (IH, d, J= 8.7 Hz),

7.08-7.09 (2H, m), 7.31 (IH, s), 7.66 (IH, dd, J= 3.0, 9.0 Hz), 7.76 (IH, d, J= 2.4 Hz), 7.86 (IH, m), s 8.02 (2H, s), 8.04 (IH, s), 8.25 (IH, m), 8.51 (IH, s).

Synthesis Example 105

Production of 4-{[7-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]methyl}benzoic acid

The title compound (120 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-{[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]methyl}benzoate (150 mg) and IN aqueous sodium hydroxide solution (3 mL).

¹H-NMR (DMSOd₆) δ 2.17 (3H₅ s), 2.43 (3H, s), 5.80 (2H, s), 6.93 (IH, d, J= 8.7 Hz), 7.13-7.23 (2H, m), 7.37 (2H, d, J= 7.8 Hz), 7.84 (IH, dd, J= 2.1, 9.0 Hz), 7.92-7.97 (2H, m), 8.15 (IH, d, J= 2.1 Hz), 8.32 (IH, s), 8.67 (IH, s), 10.09 (IH, s), 13.0 (IH, br s). Synthesis Example 106

Production of 4-{[7-({3-cUoro4-[(3-fluoroberizyl)oxy]phenyl}amrno)-2H-pyrazolo[4,3- d]pyrirrήdin-2-yl]methyl}-N-(2-methoxyethyl)benzarnide

A solution of 4-{[7-({3-cMoro-4-[(3-fluoroberizyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidrn-2-yl]methyl}benzoic acid (45 mg), 2-methoxyethylamine (9 mg), 1- hydroxybenzotriazole (18 mg), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (26 mg) and triethylamine (0.08 mL) inN,N-dimethylformamide (2 mL) was stirred at room temperature for 30 hrs. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (basic 5 silica gel; ethyl acetate) to give the title compound (115 mg) as a pale-yellow solid.

¹H-NMR (CDCl₃) δ 3.38 (3H, s), 3.54-3.57 (2H, m), 3.63-3.68 (2H, m), 5.12 (2H, s), 5.60 (2H, s), 6.53 (IH, br s), 6.97 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.20-7.40 (3H, m), 7.31 (IH, d, J= 8.4 Hz), 7.64 (IH, d, J= 8.7 Hz), 7.65 (IH, d, J= 8.4 Hz), 7.79 (IH, d, J= 8.4 Hz), 8.00-8.01 (2H, m), 8.50 (lH, s). i o Synthesis Example 107

Production of N-(2-methoxyethyl)-4-{[7-({3-methyl-4-[(6-methylpyrio!M-3-yl)oxy]phenyl}amino)- 2H-pyrazolo[4_s3-d]pyrimidin-2-yl]methyl}benzamide

The title compound (30 mg) was obtained as white crystals by the reaction in the same5 manner as in Synthesis Example 106 using 4-{[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}arnino)-2H-pyrazolo[4,3-d]pyrirnidin-2-yl]methyl}benzoic acid (45 mg), 2- methoxyethylamine (10 mg), 1 -hydroxybenzotriazole (20 mg), l-[3-(dimethylamino)propyl]-3- ethylcarbodϋmide hydrochloride (28 mg) and triethylamine (0.08 mL). 1H-NMR (CDCl₃) δ 2.29 (3H, s), 2.53 (3H, s), 3.38 (3H, s), 3.54-3.57 (2H, m), 3.63-3.68 (2H, m), 5.62 (2H, s), 6.51 (IH, br s), 6.93 (IH, d, J= 8.7 Hz), 7.09-7.10 (2H, m), 7.34 (2H, d, J= 8.1 Hz), 7.62-7.69 (2H, m), 7.76 (IH, m), 7.80 (IH, d, J= 8.1 Hz), 8.02 (IH, s), 8.26 (IH, m), 8.51 (IH, s). Synthesis Example 108

Production of N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H- pyrazolo[4,3-d]pyrimidm-7-amine

(i) Production of 7-(methyliMo)-2-(4-nitrophenyl)-2H-pyrazolo[4,3-d]pyriinidine

To a solution of 7-(methyltMo)-lH-pyrazolo[4,3-d]pyrirnidine (500 mg) inN,N- dimethylformamide (10 mL) was added potassium tert-butoxide (405 mg) under ice-cooling, and the mixture was stirred at room temperature for 10 min. Subsequently, 1 -fluoro-4-nitrobenzene

(465 mg) was added, and the mixture was stirred at 70°C for 30 min. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title compound (860 mg) as brown crystals. 1H-NMR (DMSOd₆) δ 2.72 (3H, s), 8.39 (2H, d, J= 8.7 Hz), 8.46 (2H, d, J= 8.7 Hz), 8.76 (IH, s),

9.64 (IH, s).

(ϋ) Production of N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H- pyrazolo [4,3 -d]pyrimidin-7-amine

The title compound (667 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methylthio)-2-(4-nitiOphenyl)-2H-pyrazolo[4,3- djpyrimidine (430 mg), 3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]aniline (321 mg) and pyridine hydrochloride (259 mg).

¹H-NMR (CDCl₃) δ 2.32 (3H, s), 2.54 (3H, s), 6.95 (IH, d, J= 9.0 Hz), 7.07-7.15 (2H, m), 7.71 (IH, dd, J= 2.7, 8.4 Hz), 7.80-7.81 (2H₃ m), 8.12 (2H, d, J= 9.3 Hz), 8.25 (IH₅ dd, J= 0.6, 2.7 Hz), 8.45 (2H, d, J= 9.3 Hz), 8.55 (IH, s), 8.57 (IH, s). Synthesis Example 109

Production of 2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2H- pyrazolo[4,3-d]pyrimidin~7-amine

To a solution of N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-2-(4-nitrophenyl)-2H- pyrazolo[4,3-d]pyrimidin-7-amine (200 mg) in a mixed solvent of ethanol/water (9:1, 6 mL) was added calcium chloride (90%, 28 mg) and the mixture was stirred at 100⁰C for 10 min. Reduced iron (90%, 164 mg) was added at room temperature, and the mixture was stirred at 100⁰C for 5 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methylene chloride =10/1) to give the title compound (140 mg) as a white solid. 1H-NMR (DMSOd₆) δ 2.20 (3H, s), 2.44 (3H, s), 5.55 (2H, s), 6.71-6.74 (2H, m), 6.95-6.98 (IH, m), 7.18-7.23 (2H, m), 7.73-7.76 (2H, m), 7.901 (IH, m), 8.03 (IH, br s), 8.18 (IH, br s), 8.34 (IH, br s), 8.94 (IH, br s), 10.05 (IH₅ br s). Synthesis Example 110

5 Production of 2-me1iioxy-N-{4-[7-({3-me1hyl-4-[(6-me1b.ylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]phenyl}acetarnide

The title compound (64 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrirrddin-7-amine (100 mg), methoxyacetic acid (30 mg), 1- i o hydroxybenzotriazole (48 mg), 1 -[3-(dimethylammo)propyl]-3-ethylcarbodiimide hydrochloride

(68 mg) andtriethylamine (0.20 mL).

¹H-NMR (CDCl₃) δ 2.26 (3H, s), 2.53 (3H, s), 3.55 (3H, s), 4.07 (2H, s), 6.92 (IH, d, J= 8.7 Hz),

7.12-7.25 (2H, m), 7.35-7.45 (3H, m), 7.70-7.83 (4H, m), 8.19 (IH, d, J= 2.4 Hz), 8.44 (2H, s), 8.50

(IH, s). is Synthesis Example 111

Production of 2-(N,N-dknethylamino)-N-{4-[7-({3-methyl-4-[(6--methylpyridin-3- yl)oxy]phenyl} amino)-2H-pyrazolo [4,3 -d]pyrimidin-2-yl]phenyl} acetamide

The title compound (60 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 2-(4-arriinophenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine (100 mg), N,N-dimethylglycine 5 hydrochloride (46 mg), 1-hydroxybenzotriazole (48 mg), l-[3-(dimethylamino)propyl]-3- ethylcarbodϋmide hydrochloride (68 mg) and triethylamine (0.20 mL). 1H-NMR (CDCl₃) δ 2.31 (3H, s), 2.43 (6H, s), 2.53 (3H, s), 3.14 (2H, s), 6.95 (IH, d, J= 9.0 Hz), 7.09-7.11 (2H, m), 7.70-7.76 (2H, m), 7.81-7.85 (5H, m), 8.27 (IH, m), 8.43 (IH, s), 8.55 (IH, s), 9.35 (lH, br s). i o Synthesis Example 112

Production of methyl 4-({4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyriinidrn-2-yl]phenyl}arnino)-4-oxobutanoate

The title compound (175 mg) was obtained as white crystals by the reaction in the same 5 manner as in Synthesis Example 106 using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrirnidin-7-amine (150 mg), succinic acidmonomethyl ester (66 mg), 1-hydroxybenzotriazole (72 mg), l-[3-(dimemylamino)propyl]-3-emylcarbodiimide hydrochloride (102 mg) and triethylamine (0.30 mL). 1H-NMR (CDCl₃) δ 2.30 (3H, s), 2.53 (3H, s), 2.73-2.75 (2H, m), 2.79-2.81 (2H, m), 3.75 (3H, s), 6.94 (IH, d, J= 8.7 Hz), 7.10-7.12 (2H, m), 7.69-7.74 (3H, m), 7.79-7.82 (4H, m), 8.08 (IH, br s), 8.27 (IH, dd, J= 0.6, 2.4 Hz), 8.42 (IH, s), 8.53 (IH, s). Synthesis Example 113

5 Production of 4-({4-[7-({3-me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]phenyl} arnino)-4~oxobutanoic acid

The title compound (98 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-({4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammo)-2H-pyrazolo[4,3-d]pyrimi^ i o and IN aqueous sodium hydroxide solution (0.5 rnL).

¹H-NMR (DMSOd₆) δ 2.21 (3H, s), 2.44 (3H, s), 2.50-2.61 (4H, m), 6.97 (IH, d, J= 8.4 Hz), 7.20- 7.22 (2H, m), 7.81-7.93 (4H, m), 8.03-8.09 (3H, m), 8.18 (IH, m), 8.36 (IH, s), 9.13 (IH, s), 10.2 (lH, br s), 10.3 (IH, s). Synthesis Example 114

Production of 2-(2-methoxyethoxy)-N-{4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}amino)-2H-pyra2Olo[4,3-d]pyrirrddin-2-yl]phenyl}acetamide

The title compound (88 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 2-(4-aminophenyl)-N-{3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}-2H-pyrazolo[4,3-d]pyrimidin-7-amine (130 mg), (2-methoxyethoxy)acetic acid (58 5 mg), 1-hydroxybenzotriazole (62 mg), l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (88 mg) and triethylamine (0.26 mL).

¹H-NMR (CDCl₃) δ 2.30 (3H, s), 2.53 (3H, s), 3.52 (3H, s), 3.63-3.66 (2H, m), 3.80-3.82 (2H, m), 4.16 (2H, s), 6.94 (IH, d, J= 8.7 Hz), 7.07-7.10 (2H, m), 7.71 (IH, d, J= 8.7 Hz), 7.80 (IH, m), 7.83 (4H, s), 8.27 (IH, s), 8.43 (IH, s), 8.54 (IH, s), 9.16 (IH, s). i o Synthesis Example 115

Production of methyl 4-[7-({3-me1%l-4-[(6-memylpyiidm-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]benzoate

(i) Production of methyl 4-[7-(me1hylMo)-2H-pyrazolo[4,3-d]pyrirnidin-2-yl]benzoate 5 To a solution of 7-(methyliMo)-lH-pyrazolo[4,3-d]pyrimidine (100 mg) and methyl 4- fluorobenzoate (102 mg) in l-methyl-2-pyrrolidone (2 mL) was added potassium carbonate (125 mg), and the mixture was stirred at 120°C for 3 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The resultant solid was collected by filtration, washed with diisopropyl ether and dried to give the title0 compound (90 mg) as yellow crystals. ¹H-NMR (CDCl₃) δ 2.76 (3H, s), 3.98 (3H, s), 8.04 (2H, d, J= 8.4 Hz), 8.24 (2H, d, J= 8.4 Hz), 8.63 (IH, s), 8.77 (IH, s).

(ii) Production of methyl 4-[7-({3-me1hyl-4-[(6-me1iiylpyridin-3-yl)oxy]phenyl}amino)-2H- pyrazolo[4,3-d]pyrimidin-2-yl]benzoate

5 The title compound (135 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using methyl 4-[7-(methylthio)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzoate (115 mg), 3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]aniline (82 mg) and pyridine hydrochloride (66 mg).

¹H-NMR (CDCl₃) δ 2.32 (3H, s), 2.54 (3H, s), 3.99 (3H, s), 6.95 (IH, d, J= 8.7 Hz), 7.10-7.12 (2H, i o m), 7.73 (IH, dd, J= 2.7, 8.7 Hz), 7.81-7.82 (2H, m), 8.00 (2H₅ d, J= 8.4 Hz), 8.26 (2H, d, J= 8.4 Hz), 8.27 (IH, s), 8.55 (IH, s), 8.56 (IH, s). Synthesis Example 116

Production of 4-[7-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}arrώio)--2H-pyrazolo[4,3- 15 d]pyrirnidin-2-yl]benzoic acid

The title compound (91 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 101 using methyl 4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}arrdno)-2H-pyrazolo[4,3-d]pyrirnidin-2-yl]benzoate (110 mg) and IN aqueous sodium hydroxide solution (0.4 mL). 0 ¹H-NMR (DMSO-d_δ) δ 2.21 (3H₅ s), 2.44 (3H, s), 6.98 (IH, d, J= 9.0 Hz), 7.21-7.26 (2H, m), 7.90 (IH, dd, J= 2.7, 8.7 Hz), 8.03 (IH, m), 8.12-8.22 (6H, m), 8.38 (IH, s), 9.30 (IH, s), 10.3 (IH, br s).

Synthesis Example 117

Production of N-(2-methoxye1iiyl)-4-[7-({3-me1iiyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)- 2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzamide

The title compound (63 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 106 using 4-[7-({3-methyl-4-[(6-methylpyridin-3- yl)oxy]phenyl}ammo)-2H-pyrazolo[4,3-d]pyrimidin-2-yl]benzoic acid (75 mg), 2- methoxyethylamine (17 mg), 1-hydroxybenzotriazole (34 mg), l-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (48 mg) and triethylamine (0.14 mL).

¹H-NMR (CDCl₃) δ 2.31 (3H, s), 2.54 (3H, s), 3.43 (3H, s), 3.60-3.63 (2H, m), 3.69-3.74 (2H, m), 6.61 (IH, br s), 6.96 (IH, d, J= 8.7 Hz), 7.10-7.12 (2H, m), 7.72 (IH, dd, J= 2.4, 8.4 Hz), 7.81 (IH, t, J= 3.3 Hz), 8.00 (4H, s), 8.27 (IH, m), 8.53 (IH, s), 8.55 (IH, s). Synthesis Example 118

Production of {4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl} amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]phenyl}methanol

© Production of 4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzaldehyde The title compound (60 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 115 (i) using N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}- lH-pyrazolo[4,3-d]pyrimidin-7-amine (100 mg) and4-fluorobenzaldehyde (37 mg).

¹H-NMR (DMSO-de) δ 5.26 (2H, s), 7.16-7.35 (4H, m), 7.46 (IH, m), 7.93 (IH, dd, J= 2.6, 8.8 Hz),

8.18 (2H, d, J= 8.4 Hz), 8.30 (IH, d, J= 2.2 Hz), 8.38-8.43 (3H, m), 9.40 (IH, s), 10.1 (IH, s), 10.3 (IH, s).

(ϋ) Production of {4-[7-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]phenyl}methanol

To a solution of 4-[7-({3-cMoro^-[(3-fluorobenzyl)oxy]phenyl}arnino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzaldehyde (50 mg) in methanol (2 mL) was added sodium borohydride (2 mg) under ice-cooling, and the mixture was stirred for 30 min. After the completion of the reaction, the reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (tetrahydrofiiran/ethyl acetate=l/l) to give the title compound (20 mg) as a white solid.

¹H-NMR (DMSOd₆) δ 4.60 (2H, d, J= 5.8 Hz), 5.25 (2H, s), 5.38 (IH, t, J= 5.8 Hz), 7.16-7.35 (3H, m), 7.49 (IH, m), 7.56 (2H, d, J= 8.8 Hz), 7.93 (IH, m), 8.09 (2H, d, J= 8.8 Hz), 8.30 (IH, d, J= 2.4

Hz), 8.38 (IH, s), 9.22 (IH, s), 10.2 (IH, s).

Synthesis Example 119

Production ofN-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-[4-({[2- (memylsdfonyl)ethyl]amMo}methyl)pheny

To a solution of 4-[7-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- 5 d]pyrirnidin-2-yl]benzaldehyde (80 mg) and 2-(methylsulfonyl)ethylamine hydrochloride (40 mg) in N,N-dmethylformamide (2 mL) was added acetic acid (0.02 mL), and the mixture was stirred at room temperature for 1 hr. Subsequently, sodium triacetoxyborohydride (54 mg) was added, and the mixture was stirred at the same temperature for 2 hrs. After the completion of the reaction, saturated aqueous sodium hydrogen carbonate was added, and the mixture was concentrated under i o reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/methanol=5/l) to give the title compound (70 mg) as a white solid. 1H-NMR (CDCl₃) δ 3.02 (3H, s), 3.22 (4H, s), 3.92 (2H, s), 5.17 (2H, s), 6.98-7.04 (2H, m), 7.21-

15 7.26 (3H, m), 7.36 (IH, m), 7.52 (2H, d, J= 8.1 Hz), 7.68-7.71 (2H, m), 7.84 (2H, d, J= 8.1 Hz), 8.05 (IH, d, J= 2.4 Hz), 8.45 (IH, s), 8.54 (IH, s). Synthesis Example 120

Production of 2-({4-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]benzyl} amino)ethanol

The title compound (83 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 119 using 4-[7-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}ammo)-2H-pyrazolo[4,3-d]pyrin3idm-2-yl]benzaldehyde (120 mg), ethanolamine (23 mg) and sodium triacetoxyborohydride (134 mg).

¹H-NMR (DMSOd₆) δ 2.59 (2H, t, J= 6.0 Hz), 3.48 (2H, m), 3.80 (2H,s), 4.51 (IH, br s), 5.25 (2H, s), 7.16-7.34 (5H, m), 7.46 (IH, m), 7.57 (2H, d, J= 7.8 Hz), 7.91 (IH, dd, J= 1.8, 9.0 Hz), 8.07 (2H, d, J= 7.8 Hz), 8.30 (IH, d, J= 1.8 Hz), 8.38 (IH, s), 9.21 (IH₃ s), 10.2 (IH, s). Synthesis Example 121

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(4-{[(2-morpholin-4- ylethyl)amino]methyl}phenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-amine

The title compound (68 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 119 using 4-[7-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}amrno)-2H-pyrazolo[4^^^ (80 mg), N-(2- aminoethyl)moφholine (33 mg) and sodium triacetoxyborohydride (54 mg). 1H-NMR (CDCl₃) δ 2.44 (4H, t, J= 4.5 Hz), 2.53 (2H, t, J= 6.0 Hz), 2.74 (2H, t, J= 6.0 Hz)₅ 3.70 5 (4H, t, J= 4.5 Hz), 3.91 (2H, s), 5.16 (2H, s), 6.98 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.19-7.25 (3H, m), 7.35 (IH, m), 7.52 (2H, d, J= 8.7 Hz), 7.67-7.71 (2H, m), 7.82 (2H, d, J= 8.7 Hz), 8.04 (IH, d, J= 2.4 Hz), 8.43 (IH, s), 8.52 (IH, s). Synthesis Example 122

i o Production of 2-[7-({3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyrazolo[4,3- djpyrirnidin- 1 -yl] ethanol

2-[7-({3-CMoro-4-[(3-fluorobenzyl)oxy]phenyl}arr^ yl]ethyl benzoate was obtained as a mixture with 1 -methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using 2-[7-(methyltMo)-lH-pyrazolo[4,3-d]pyrimidin-l- 25 yl]ethyl benzoate (130 mg), 3-chloro4-[(3-fluorobenzyl)oxy]aniline (104 mg) and pyridine hydrochloride (72 mg).

The title compound (60 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (0.2 mL). ¹H-NMR (DMSOd₆) δ 3.87-3.93 (2H, m), 4.75 (2H₅ t, J= 5.7 Hz), 5.24 (2H,s), 6.27 (IH, t, J= 3.9 Hz), 7.13-7.32 (4H, m), 7.48 (IH, m), 7.55 (IH, dd, J= 2.4, 9.3 Hz), 7.86 (IH, d, J= 1.8 Hz), 8.17 (IH, s), 8.36 (IH, s), 9.85 (IH, s). Synthesis Example 123

Production of 2-[7-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyriinidin-2-yl]ethanol

2-[7-({3-CUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3-d]pyrimidin-2- yl]ethyl benzoate was obtained as a mixture with l-methyl-2-pyrrolidone by the reaction in the i o same manner as in Synthesis Example 97 using 2-[7-(me1hyltMo)-2H-pyrazolo[4,3-d]pyrirnidin-2- yljethyl benzoate (120 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (96 mg) and pyridine hydrochloride (66 mg).

The title compound (86 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium 15 hydroxide solution (0.2 mL).

¹H-NMR (DMSOd₆) δ 3.88-3.93 (2H, m), 4.50 (2H, t, J= 5.4 Hz), 5.04 (IH, t, J= 5.7 Hz), 5.23 (2H, s), 7.14-7.32 (4H, m), 7.46 (IH, m), 7.88 (IH, dd, J= 2.7, 9.0 Hz), 8.28 (IH, d, J= 1.8 Hz), 8.31 (IH, s), 8.45 (IH, s), 10.12 (IH, s).

Synthesis Example 124

Production of 2-[7-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-lH-pyrazolo[4,3- d]pyrimidin- 1 -yl] ethanol

2-[7-({3-Me1hyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}aωino)-lH-pyrazolo[4,3- 5 d]pyrirnidin-l-yl]ethyl benzoate was obtained as a mixture with l-methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 101 using 2-[7-(methylthio)-lH-pyrazolo[4,3- d]pyrimidin-l-yl]ethyl benzoate (190 mg), 3-memyl-4-[(6-me1hylpyridin-3-yl)oxy]aniline (129 mg) and pyridine hydrochloride (105 mg).

The title compound (88 mg) was obtained as a pale-yellow solid by the reaction in the same i o manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (0.3 mL).

¹H-NMR (CDCl₃) δ 2.22 (3H, s), 2.48 (3H, s), 4.25 (2H, br s), 4.76 (2H, br s), 6.01 (IH, br s), 6.86 (IH, d, J= 8.7 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.16 (IH, dd, J= 3.0, 8.7 Hz), 7.45 (IH, dd, J= 2.7, 8.7 Hz), 7.56 (IH, d, J= 2.7 Hz), 8.05 (IH, d, J= 3.0 Hz), 8.37 (IH, s), 9.88 (IH, s). 15 Synthesis Example 125

Production of 2-[7-({3-methyl-4-[(6-memylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrirrddin-2~yl]ethanol

2-[7-({3-Me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl] ethyl benzoate was obtained as a mixture with l-methyl-2-pyrrolidone by the reaction in the same manner as in Synthesis Example 97 using 2-[7-(methylthio)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]ethyl benzoate (115 mg), 3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]aniline (78 mg) and pyridine hydrochloride (63 mg).

The title compound (95 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 101 using the above-mentioned mixture and IN aqueous sodium hydroxide solution (0.3 mL). 1H-NMR (CDCl₃) δ 2.24 (3H, s), 2.52 (3H, s), 4.16 (2H, t, J= 4.5 Hz), 4.26 (IH, br s), 4.50-4.53 (2H, m), 6.86 (IH, d, J= 8.7 Hz), 7.05-7.12 (2H, m), 7.57-7.61 (2H, m), 7.69 (IH, d, J= 2.7 Hz), 7.97 (IH, s), 8.23 (IH, m), 8.34 (IH, s). Synthesis Example 126

Production of 3-[7-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-lH-pyrazolo[4,3- djpyrimidin- 1 -yl]propanol

The title compound (240 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 122 using 3-[7-(methylthio)-lH-pyrazolo[4,3-d]pyrirnidiri-l- yl]propyl benzoate (623 mg), 3-cUoro-4-[(3-fluorobenzyl)oxy]anihne (477 mg) and pyridine hydrochloride (329 mg) and IN aqueous sodium hydroxide solution (0.5 mL). 1H-NMR (DMSOd₆) δ 1.97-2.04 (2H, m), 3.25-3.28 (2H, m), 4.71(2H, t, J= 6.6 Hz)₃ 5.27 (2H,s), 5.44 (IH, t, J= 4.8 Hz), 7.16-7.34 (4H, m), 7.48 (IH, m), 7.57 (IH, dd, J= 2.7, 9.0 Hz), 7.82 (IH, d, J= 2.4 Hz), 8.19 (IH, s), 8.35 (IH, s), 9.22 (IH, s). Synthesis Example 127

Production of 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-2H-pyrazolo[4,3- d]pyrimidin-2-yl]propanol

The title compound (512 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 123 using 3-[7-(me1hyliMo)-2H-pyrazolo[4,3-d]pyrirnidin-2- yljpropyl benzoate (556 mg), 3-cMoro-4-[(3-fluorobenzyl)oxy]aniline (426 mg), pyridine hydrochloride (293 mg) and IN aqueous sodium hydroxide solution (10 mL).

¹H-NMR (DMSO-d_δ) δ 2.06-2.13 (2H, m), 3.41-3.46 (2H, m), 4.53 (2H, t, J= 6.9 Hz), 4.70 (IH, t,

J= 5.4 Hz), 5.24 (2H, s), 7.16-7.33 (4H, m), 7.46 (IH, m), 7.89 (IH, dd, J= 2.4, 9.0 Hz), 8.28 (IH, d, J= 2.4 Hz), 8.32 (IH, s), 8.51 (IH, s), 10.12 (IH, s).

Synthesis Example 128

Production of 4-{3-cWoro^-[(3-fluorobenzyl)oxy]phenyl}-5,6-dihydro-4H-pyrazolo[4,5,l- dejpteridine

A solution of 2-[7-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-lH-pyrazolo[4,3- 5 d]pyrimidin-l-yl]ethanol (40 mg), l,r-(azodicarbonyl)dipiperidine (48 mg) andtributylphosphine (40 mg) in tetrahydrofuran (2 mL) was stirred at room temperature for 15 hrs. After the completion of the reaction, water was added to the reaction mixture and the mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel i o column chromatography (hexane/ethyl acetate=4/l — > 1/4) to give the title compound (31 mg) as a white solid.

¹H-NMR (CDCl₃) δ 4.32 (2H, dd, J= 5.0, 6.6 Hz), 4.62 (2H, dd, J= 5.0, 6.6 Hz), 5.19 (2H, s), 7.04 (IH, d, J= 9.2 Hz), 7.05 (IH, m), 7.18-7.26 (2H, m), 7.32-7.43 (2H, m), 7.55 (IH, d, J= 2.6 Hz), 8.09 (IH, s), 8.51 (IH, s).

15 Synthesis Example 129

Production of 4-{3-meώyl-4-[(6-metiiylpyridin-3-yl)oxy]phenyl}-5,6-dihydro-4H-pyrazolo[4,5,l- de]pteridine

The title compound (21 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 128 using 2-[7-({3-methyl-4-[(6-methylpyridin-3- 5 yl)oxy]phenyl}arnmo)-lH-pyrazolo[4,3-d]pyrimidin-l-yl]ethanol (30 mg), 1,1 '- (azodicarbonyl)dipiperidine (40 mg) and tributylphosphine (32 mg).

¹H-NMR (CDCl₃) δ 2.34 (3H₅ s), 2.55 (3H, s), 4.36 (2H, t, J= 5.7 Hz), 4.64 (2H, t, J- 5.7 Hz), 6.92 (IH, d, J= 8.4 Hz), 7.13 (IH, d, J= 8.4 Hz), 7.20 (IH, dd, J= 2.7, 8.4 Hz), 7.27 (IH, dd, J= 2.4, 8.4 Hz), 7.41 (IH, d, J= 2.4 Hz), 8.09 (IH, s), 8.30 (IH, d, J= 2.7 Hz), 8.53 (IH, s). i o Synthesis Example 130

Production of 6-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-l,3,5,6,9a- pentaazabenzo[cd]azulene

The title compound (29 mg) was obtained as a pale-yellow solid by the reaction in the same 15 manner as in Synthesis Example 128 using 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)- lH-pyrazolo[4,3-d]pyrimidin-l-yl]propanol (60 mg), l,r-(azodicarbonyl)dipiperidine (70 mg) and tributylphosphine (57 mg).

¹H-NMR (CDCl₃) δ 2.49-2.56 (2H, m), 4.03 (2H, m), 4.62 (2H, t, J= 5.7 Hz), 5.19 (2H, s), 7.02 (IH, d, J= 8.7 Hz), 7.05 (IH, m), 7.15 (IH, dd, J= 2.7, 9.0 Hz), 7.21-7.26 (2H, m), 7.35-7.42 (2H, m), 8.12 (IH, s), 8.37 (IH, s).

Synthesis Example 131

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-(3-{[2- 5 (me1hylsulfonyl)ethyl]anmo}propyl)-^^

A solution of 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}aniino)-2H-pyrazolo[4,3- d]pyrknidin-2-yl]propanol (50 mg), N-[2-(methylsulfonyl)e1iiyl]-2-nitrobenzenesulfonamide (47 mg), l,l'-(azodicarbonyl)dipiperidine (59 mg) andtributylphosphine (47 mg) interrahydrofuran (2 mL) was stirred at room temperature for 4 hrs. After the completion of the reaction, water was i o added to the reaction mixture and the mixture was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=4/l -> 1/4) to giveN-{3-[7-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}ammo)-2H-pyrazolo[4,3-d]pvrimidin-2-yl]propyl}-N-[2-

15 (metiiylsulfonyl)ethyl]-2-nitrobenzenesulfonamide. To a solution of this compound in tetrahydrofuran (2 mL) were added 2-mercaptoethanol (12 mg) and l,8-diazabicyclo[5.4.0]undec- 7-ene (23 mg), and the mixture was stirred at room temperature for 3 hrs. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/l) to give the title compound (34 mg) as a white solid.

¹H-NMR (CDCl₃) δ 2.05-2.14 (2H, m), 2.57 (2H, t, J- 6.3 Hz)₅3.08 (3H, s), 3.14-3.16 (2H, m), 3.22-3.26 (2H, m), 4.54 (2H, t, J= 6.3 Hz), 5.16 (2H, s), 6.97 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.20- 7.26 (3H, m), 7.36 (IH, dt, J= 6.3, 7.8 Hz), 7.71 (IH, dd, J= 2.7, 9.0 Hz), 7.99 (2H, s), 8.09 (IH, d, J= 2.7 Hz), 8.49 (IH, s). Synthesis Example 132

Production of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-{3-[(2-morpholin-4- ylethyl)amino]propyl} -2H-pyrazolo[4,3 -d]pyrimidin-7-amine

The title compound (32 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 131 using 3-[7-({3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}amino)- 2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol (60 mg), N-(2-moφholin-4-ylethyl)-2- nitrobenzenesulfonamide (53 mg), l,r-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg), 2-mercaptoethanol (12 mg) and l,8-diazabicyclo[5.4.0]undec-7-ene (23 mg). 1H-NMR (CDCl₃) δ 2.42-2.51 (8H, m), 2.59-2.72 (4H, m), 3.70 (4H, t, J= 4.8 Hz), 4.51 (2H, t, J= 6.8 Hz), 5.15 (2H, s), 6.97 (IH, d, J= 8.8 Hz), 7.02 (IH, m), 7.19-7.26 (2H, m), 7.31-7.42 (2H, m), 7.66 (2H, m), 7.98 (IH, s), 8.01 (IH, d, J= 2.8 Hz), 8.49 (IH, s). Synthesis Example 133

Production of N-{3-cUoro4-[(3-fluoroben2yl)oxy]phenyl}-2-{3-[(2-methoxyethyl)amino]propyl}- 2H-pyrazolo[4,3-d]pyrimidin-7-amine

The title compound (26 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 131 using 3-[7-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)- 2H-pyrazolo[4,3-d]pyrimidin-2-yl]propanol (60 mg), N-(2-methoxyethyl)-2- nitrobenzenesulfonamide (44 mg), l₅r-(azodicarbonyl)dipiperidine (71 mg), tributylphosphine (57 mg), 2-mercaptoethanol (12 mg) and l,8-diazabicyclo[5.4.0]undec-7-ene (23 mg). 1H-NMR (CDCl₃) δ 2.14-2.18 (2H, m), 2.61 (2H, t, J= 6.6 Hz), 2.76 (2H, t, J= 5.1 Hz), 3.37 (3H, s), 3.50 (2H, t, J= 5.1 Hz), 4.52 (2H, t, J= 6.6 Hz), 5.15 (2H, s), 6.97 (IH, d, J= 9.0 Hz), 7.01 (IH, m), 7.18-7.26 (4H, m), 7.35 (IH, m), 7.58 (IH, br s), 7.65 (IH, dd, J= 2.4, 8.7 Hz), 7.99-8.00 (2H, m), 8.48 (IH, s). Synthesis Example 134

Production of 2-{[2-cMoro-4-(lH-pyrazolo[4,3-d]pyrimidin-7- ylamino)phenoxy]methyl}benzonitrile

The title compound (96 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(memyltMo)-lH-pyrazolo[4,3-d]pyrirnidine (80 mg), 2- [(4-amino-2-chlorophenoxy)methyl]benzonitrile (125 mg) and pyridine hydrochloride (83 mg). ¹H-NMR (DMSOd₆) δ 2.23 (3H, s), 5.26 (2H, s), 7.09 (IH, d, J= 8.7 Hz), 7.54-7.77 (5H, m), 7.92 (IH, d, J= 8.7 Hz), 8.20 (IH, br s), 8.34 (IH, br s), 9.45 (IH, br s), 12.8 (IH, br s). Synthesis Example 135

Production of 2- { [2-methyl-4-( 1 H-pyrazolo [4,3 -d]pyrimidin-7- ylamino)phenoxy]methyl}benzonitrile

The title compound (110 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methylthio)-lH-pyrazolo[4,3-d]pyrimidine (80 mg), 2-[(4-amino-2-methylphenoxy)methyl]benzonitrile (115 mg) and pyridine hydrochloride (83 mg). 1H-NMR (DMSOd₆) δ 2.23 (3H, s), 5.26 (2H, s), 7.09 (IH, d, J= 8.7 Hz), 7.54-7.77 (5H, m), 7.92

(IH, d, J= 8.7 Hz), 8.20 (IH, br s), 8.34 (IH, br s), 9.45 (IH, br s), 12.8 (IH, br s).

Synthesis Example 136

Production of 3-[2-cUoro-4-(lH-pyrazolo[4,3-d]pyrimidin-7-ylamJno)phenoxy]benzoni1rile

The titie compound (89 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methyltMo)-lH-pyra2»lo[4,3-d]pyrimidine (80 mg), 3- 5 (4-amino-2-chlorophenoxy)benzonitrile (117 mg) and pyridine hydrochloride (83 mg).

¹H-NMR (DMSOd₆) δ 7.26-7.35 (2H, m), 7.46 (IH, m), 7.55-7.59 (2H, m), 7.89 (IH, m), 8.39 (IH, br s), 8.46 (2H, s), 10.16 (IH₅ br s), 12.6 (IH, br s).

Synthesis Example 137

i o Production of 3-[2-methyl-4-(lH-pyrazOlo[4,3-d]pyrirrύdin-7-ylammo)phenoxy]benzoni1rU

The title compound (98 mg) was obtained as a pale-yellow solid by the reaction in the same manner as in Synthesis Example 97 using 7-(methylMo)-lH-pyrazolo[4,3-d]pyrirnidine (80 mg), 3-

(4-amino-2-methylphenoxy)benzonitrile (108 mg) and pyridine hydrochloride (83 mg).

¹H-NMR (DMSOd₆) δ 2.18 (3H, s), 7.09 (IH, d, J= 8.7 Hz), 7.24 (IH, m), 7.37 (IH, m), 7.53-7.59 15 (2H, m), 7.86 (IH, d, J= 8.7 Hz), 7.93 (IH, br s), 8.32 (IH, br s), 8.42 (IH, br s), 9.85 (IH, br s),

12.2 (lH, br s).

Synthesis Example 138

Production of 2-{2-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrhnidin-5-yl]ethoxy}ethanol

(i) Production of 2-[2-(4-cMoro-5H-pyπ-olo[3,2-d]pyrirnidin-5-yl)ethoxy]efhyl benzoate 5 To a solution of 2,2'-oxydiethanol (2.12 g) in pyridine (20 mL) was added benzoic anhydride (4.52 g) by small portions under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 18 hrs. Pyridine was evaporated under reduced pressure and the obtained residue was diluted with diethyl ether (20 mL). 5% Aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with diethyl ether (100 mLx3). The i o solvent was evaporated under reduced pressure, and the obtained residue was subj ected to silica gel chromatography (eluenthexane/ethyl acetate=95/5 -» 40/60). The object fraction was concentrated under reduced pressure and dried to give 2-(2-hydroxyethoxy)ethyl benzoate (2.21 g). To a solution of the obtained 2-(2-hydroxyethoxy)ethyl benzoate (2.10 g) in dichloromethane (10 mL) were added l-iodopyrrolidine-2,5-dione (2.70 g) and triphenylphosphine (3.14 g) by small portions under is ice-cooling, and the mixture was stirred for 14 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (120 mLx3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluenthexane/ethyl acetate=100/0 — > 60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(2- iodoethoxy)ethyl benzoate (2.05 g) as a colorless transparent oil.

To a suspension of 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (0.659 g) inN,N- dimethylformamide (5.0 mL) was added cesium carbonate (3.13 g) under ice-cooling, and the 5 reaction mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 2-(2~iodoethoxy)ethyl benzoate (1.45 g) prepared above, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (150 mLx3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium i o sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluenthexane/ethyl acetate=95/5 — > 60/40). The object fraction was concentrated under reduced pressure and dried to give the title compound (0.822 g) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 3.718 (2H, dt, J= 3.0, 6.6 Hz), 3.887 (2H, t, J= 5.1 Hz), 4.412 (2H, dt, J= 3.0, is 6.6 Hz), 4.680 (2H, t, J= 5.1 Hz), 6.566 (IH, d, J= 3.3 Hz), 7.404-7.462 (2H, m), 7.542-7.600 (2H, m), 7.944-7.982 (2H, m), 8.665 (IH, s).

(ϋ) Production of 2-{2-[4-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy}ethyl benzoate

To a solution of 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate 0 (802 mg) in l-methyl-2-pyrrolidone (8.0 mL) was added 3-cMoro-4-[(3-fluorobenzyl)oxy]aniline

(745 mg), and the mixture was stirred in an oil bath at a temperature of 100⁰C for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with a mixed solvent (50 mL^χ3) of ethyl acetate/tetrahydrofuran (3/1). The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (1141 mg) as a yellow amorphous solid. 1H-NMR (CDCl₃) δ 3.901-3.931 (2H, m), 4.036 (2H₅1, J= 4.2 Hz)₅4.452-4.483 (2H₅ m), 4.540 (2H, t, J= 4.2 Hz), 5.033 (2H₅ s), 6.590 (IH, d, J= 3.0 Hz)₅6.704 (IH, d, J= 9.0 Hz)₅7.005 (IH₅ td, J= 1.8, 7.5 Hz), 7.164-7.372 (7H₅ m), 7.511 (IH₅ tt, J= 1.8, 7.5 Hz), 7.679 (IH, d, J= 3.0 Hz)₅7.769 (IH₅ t, J= 1.8 Hz)₅ 7.788 (IH, t, J= 0.6 Hz), 8.431 (IH, s), 8.511 (IH, s). (iii) Production of 2-{2-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pvrirnidin-5-yl]ethoxy}ethanol

To a solution of 2-{2-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H- pvrrolo[3,2-d]pyrirnidin-5-yl]ethoxy}ethyl benzoate (760 mg) in tetrahydrofuran (7.0 mL) was added IN aqueous sodium hydroxide solution (7.0 mL), and the mixture was stirred at room temperature for 14 hrs. IN Hydrochloric acid (7.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 10 min. and extracted with a mixed solvent (100 mLx3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography (eluent: ethyl acetate/methanol=100/0 -> 90/10). The object fraction was concentrated under reduced pressure. A mixed solvent of ethanol/isopropyl ether (1/4) was added to the residue, and the mixture was heated to 80⁰C and then allowed to cool to room temperature. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (431 mg) as white powder crystals. ¹H-NMR (DMSO-4) δ 3.471-3.478 (4H, m), 3.817 (2H₃ t, J= 4.6 Hz), 4.616 (2H, t, J= 4.6 Hz), 4.681-4.712 (IH, m), 5.234 (2H, s), 6.480 (IH, d, J= 3.2 Hz), 7.173-7.212 (2H, m), 7.289-7.339 (2H, m), 7.433-7.523 (2H, m), 7.641 (IH, d, J= 3.2 Hz), 7.829 (IH, d, J= 3.2 Hz), 8.271 (IH, s), 8.698 (IH, s). 5 melting point: 168-169⁰C

Synthesis Example 139

Production of 4-[4-({3-cMoro-4-[3-(Mfluoromethyl)phenoxy]phenyl}amiao)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]butan- 1 -ol i o (i) Production of 4-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)butyl acetate

To a suspension of 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (0.768 g) in N₅N- dimethylformamide (10 mL) was added cesium carbonate (2.01 g) under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 15 min. 4-Bromobutyl acetate (1.26 g) was added dropwise to the reaction mixture, and the mixture was stirred at room

15 temperature for 30 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (80 mL), and extracted with ethyl acetate (100 mLx3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 0/100). The object fraction was 0 concentrated under reduced pressure and dried to give the title compound (1.084 g) as a colorless transparent oil.

¹H-NMR (CDCl₃) δ 1.636-1.730 (2H, m), 1.874-1.971 (2H, m), 2.047 (3H, s), 4.098 (2H, t, J= 6.3 Hz)₅4.512 (2H, t, J- 6.3 Hz), 6.718 (IH, d, J= 3.3 Hz), 7.482 (IH, d, J= 3.3 Hz), 8.690 (IH, s). (ϋ) Production of 4-[4-({3-cUoro-4-[3-(tiifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]butyl acetate

To a solution of 4-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)butyl acetate (302 mg) in isopropyl alcohol (2.24 mL) was added 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421 mg), and the mixture was stirred in an oil bath at a temperature of 100⁰C for 3.5 hrs. The reaction mixture was allowed to cool to room temperature, 5% aqueous sodium hydrogen carbonate solution (35 mL) was added, and the mixture was extracted with ethyl acetate (50 mLx3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (293 mg) as a white powder.

¹H-NMR (CDCl₃) δ 1.624-1.714 (2H, m), 1.924-2.005 (2H, m), 2.005 (3H, s), 4.108 (2H, t, J= 6.0 Hz), 4.342 (2H, t, J= 6.0 Hz), 6.573 (IH, d, J= 3.3 Hz), 7.054 (IH, s), 7.083-7.471 (7H, m), 7.793 (IH, d, J= 3.3 Hz), 8.526 (IH, s). (iii) Production of 4-[4-({3-cUoro-4-[3-(Mfluorome1hyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]butan-l-ol

To a solution of 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyiimidin-5-yl]butyl acetate (281 mg) intetrahydrofuran (4.0 mL) was added IN aqueous sodium hydroxide solution (2.8 mL), and the mixture was stirred at room temperature for 4.5 hrs. IN Aqueous hydrochloric acid solution (2.8 mL) was added, and the mixture was stirred for 15 min. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL><3). The organic layer was washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine and dried over anhydrous 5 magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 0/100). The object fraction was concentrated under reduced pressure and dried. Ethanol/diisopropyl ether (5/95) was added to the residue, and the mixture was stirred with heating to 80⁰C, allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtration. The obtained i o precipitate was washed with diisopropyl ether and dried under reduced pressure to give the title compound (214 mg) as white powder crystals.

¹H-NMR (DMSOd₆) δ 1.240-1.331 (2H, m), 1.690-1.782 (2H, m), 3.324-3.361 (2H, m), 4.473 (IH, br s), 4.540 (2H₃1, J- 6.0 Hz)₅ 6.492 (IH, d, J= 3.0 Hz), 7.200-7.254 (2H, m), 7.303 (IH, d, J= 9.0 Hz), 7.472 (IH, d, J= 9.0 Hz)₃7.621 (IH₃1, J= 9.0 Hz)₃ 7.653-7.713 (2H, m), 7.970 (IH, s), 8.351 is (IH₃ s)₃ 8.632 (IH, s).

Synthesis Example 140

Production of 3 -(2-chloro-4- { [5-(2-hydroxyethyl)-5H-pyrrolo [3 ,2-d]pyrimidin-4- yl]amino}phenoxy)benzonitrile 0 (i) Production of 2-(4-{[3-cMoro-4-(3-cyanophenoxy)phenyl]ajχdno}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)efhyl benzoate

To a suspension of 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (141 nig) inN,N- dimethylformamide (2.5 mL) was added cesium carbonate (358 mg) under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 15 min. To the reaction 5 mixture was added 2-iodoethyl benzoate (298 mg), and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution

(50 mL), and extracted with ethyl acetate (50 mLx3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel i o chromatography (eluenthexane/ethyl acetate=95/5 -> 60/40). The object fraction was concentrated under reduced pressure and dried to give 2-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)e1hyl benzoate (205 mg) as a colorless transparent oil.

The title compound (311 mg) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 42 (ϋ) using 3-(4-amino-2-chlorophenoxy)benzonitrile (211 mg) 15 and a solution of 2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl benzoate (205 mg) in 1- methyl-2-pyrrolidone (1.3 mL).

¹H-NMR (CDCl₃) δ 4.693 (4H, s), 6.688 (IH, d, J= 3.0 Hz), 7.086-7.497 (8H, m), 7.609-7.727 (2H, m), 7.962 (2H, d, J= 6.9 Hz), 8.024 (2H, d, J= 6.9 Hz), 8.569 (IH, s).

(ii) Production of 3-(2-cMoro-4-{[5-(2-hydroxyethyl)-5H-pvπ-olo[3,2-d]pyrimidin-4- 0 yl]arnino}phenoxy)benzonitrile

The title compound (187 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 138 (iii) using 2-(4-{[3-chloro-4-(3- cyanophenoxy)phenyl]amino}-5H-pyπ^{^}olo[3,2-d]pyrimidin-5-yl)ethyl benzoate (310 mg). ¹H-NMR (DMSOd₆) δ 3.977-3.990 (2H, m), 4.542 (2H, br s), 6.470 (IH, d, J= 3.0 Hz), 7.162-7.24 (3H, m), 7.421-7.625 (3H, m), 7.645 (IH, d, J= 7.2 Hz), 7.989 (IH, d, J= 3.0 Hz), 8.078 (IH, d, J= 3.0 Hz), 8.368 (IH, s), 10.10 (IH, br s). Synthesis Example 141

Production of 3-[2-cMoro4<{5-[2-(2-hydroxyetiioxy)e%l]-5H-pyrrolo[3,2-d]pyrimdin4- yl} amino)phenoxy]benzonitrile

(i) Production of 2-[2-(4-{[3-cMoro-4-(3-cyanophenoxy)phenyl]arnino}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethoxy]ethyl benzoate i o The title compound (117 mg) was obtained as a pale brown solid by the reaction in the same manner as in Synthesis Example 138 (ϋ) using 2-[2-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy] ethyl benzoate (130 mg) and 3-(4-amino-2-chlorophenoxy)benzonitrile (112 mg).

¹H-NMR (CDCl₃) δ 4.051-4.077 (2H, m), 4.206 (2H, t, J= 4.2 Hz), 4.582-4.599 (2H, m), 4.610 (2H, t, J= 4.2 Hz), 6.781 (IH, d, J= 3.0 Hz), 6.904 (IH, d, J- 9.0 Hz), 7.195 (IH, td, J= 1.8, 7.5 Hz), 15 7.360-7.568 (7H, m), 7.709 (IH, tt, J= 1.8, 7.5 Hz), 7.872 (IH, d, J= 3.0 Hz), 7.975 (IH, 1, J= 1.8

Hz), 7.968 (IH, t, J= 0.6 Hz), 8.531 (IH, s), 8.671 (IH, s).

(ϋ) Production of 3-[2-cMoro-4<{5-[2-(2-hydroxye1hoxy)e1hyl]-5H-pyrrolo[3,2-d]pyrirrύdin-4- yl} arrώio)phenoxy]benzonitrile

The title compound (52 mg) was obtained as a pale-yellow powder by the reaction in the 0 same manner as in Synthesis Example 138 (ϋi) using 2-[2-(4-{[3-chloro-4-(3- cyanophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyriinidin-5-yl)e1hoxy]e1hyl benzoate (92 mg). 1H-NMR (DMSOd₆) δ 3.578-3.693 (4H, m), 3.617 (2H, t, J= 4.8 Hz), 4.515 (2H, t, J= 4.8 Hz), 4.589-4.699 (IH, m), 6.378 (IH, d, J= 3.0 Hz), 7.153-7.181 (3H, m), 7.411-7.461 (IH₅ m), 7.553- 7.663 (2H, m), 7.840 (IH, d, J= 3.2 Hz), 8.049 (IH, d, J= 3.2 Hz), 8.377 (IH, s), 8.879 (IH, s). Synthesis Example 142

Production of 2-[4-({3-cUoro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrirnidin-

5-yl] -N-(2-hydroxyethyl)acetamide

(i) Production of ethyl [4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]acetate

To a solution of ethyl (4-cUoro-5H-pyπ-olo[3,2-d]pyrirnidin-5-yl)acetate (530 mg) in isopropyl alcohol (4.0 mL) was added 3-cHoro-4-[(3-fluorobenzyl)oxy]aniline (695 mg), and the mixture was stirred in an oil bath at a temperature of 100°C for 2.5 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mLx3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 — > 20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (743 mg) as a white solid. ¹H-NMR (CDCl₃) δ 1.298-1.344 (3H, m), 4.338 (2H₅ q₅ J= 7.2 Hz), 4.938 (2H, s), 5.132 (2H, s), 6.616 (IH, d, J= 3.4 Hz), 6.935 (IH, d, J= 8.8 Hz), 6.979-7.056 (IH, m), 7.190-7.263 (3H, m), 7.301-7.426 (2H, m), 7.638 (IH, t, J= 2.4 Hz), 8.200 (IH, s), 8.499 (IH, br s). (ϋ) Production of [4-({3-chloro4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl] acetic acid

The title compound (504 mg) was obtained as a pale-purple powder by the reaction in the same manner as in Synthesis Example 46 using ethyl [4-({3-chloro-4-[(3- fiuoroberizyl)oxy]phenyl}ammo)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]acetate (730 mg). 1H-NMR (DMSOd₆) δ 5.223 (2H₅ s), 5.282 (2H₅ s), 6.480 (IH, d, J= 3.0 Hz), 7.137-7.525 (7H, m), 7.603 (IH, d, J= 3.0 Hz), 7.666 (IH, d, J= 3.0 Hz), 8.299 (IH, s).

(iii) Production of 2-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]-N-(2-hydroxyethyl)acetamide

The title compound (39 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 36 using [4-({3-chloro-4-[(3- fluorobenzyl)oxy]phenyl}arnmo)-5H-pyrrolo[3₅2-d]pyrimidin-5-yl]acetic acid (103 mg).

¹H-NMR (DMSOd₆) δ 3.23 (2H, m), 3.46 (2H, m), 4.89 (IH, t, J= 4.5 Hz), 5.04 (2H, s), 5.22 (2H, s), 6.48 (IH, d, J= 3.0 Hz), 7.14-7.24 (2H, m), 7.29-7.33 (2H, m), 7.43-7.53 (2H, m), 7.56 (IH, d, J= 3.0 Hz), 7.85 (IH, d, J= 3.0 Hz), 8.29 (IH, s), 8.97 (IH₅ br s), 10.08 (IH, br s). Synthesis Example 143

Production of 3-[4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]propan-l -ol

To a solution of 3-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propan-l-ol (201 mg) 5 synthesized in Synthesis Example 53 (ii) in isopropyl alcohol (2.5 mL) was added 3-chloro-4-[3- (trifluoromethyl)phenoxy] aniline (381 mg), and the mixture was stirred in an oil bath at a temperature of 100°C for 2.0 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mLx3). The organic layer was washed successively with water and saturated brine and i o dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluenthexane/ethyl acetate=95/5 -> 20/80). The object fraction was concentrated under reduced pressure and dried. Ethanol/diisopropyl ether (1/9) was added to the residue, and the mixture was stirred with heating to 80°C, allowed to cool to room temperature, and stood still. The resultant precipitate was collected

15 by filtration. The obtained precipitate was washed with dϋsopropyl ether and dried under reduced pressure to give the title compound (375 mg) as white powder crystals.

¹H-NMR (DMSOd₆) δ 1.953 (2H, t, J= 5.7 Hz), 3.380 (2H, t, J= 5.7 Hz), 4.545 (2H, t, J= 6.6 Hz), 5.372 (IH, br s), 6.527 (IH, d, J= 3.0 Hz), 7.198-7.327 (3H, m), 7.470 (IH, d, J= 7.5 Hz), 7.592- 7.707 (3H, m), 7.981 (IH, d, J= 3.0 Hz)₅ 8.354 (IH, s), 9.038 (IH₅ br s). 0 Synthesis Example 144

Production of 2-{2-[4-({3-cMoro-4-[3-(trMuorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy} ethyl carbamate hydrochloride

To a solution of 2-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H- s pyrrolo [3 ,2-d]pyrimidin-5-yl] ethoxy } ethanol (84 mg) in a mixed solvent (1.0 mL) of toluene/dichloromethane (1/1) was added trichloroacetyl isocyanate (22 μL) under ice-cooling, and the mixture was stirred for 3 hrs. To the reaction mixture were added methanol (0.2 mL) and potassium carbonate (71 mg), and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (25 mL), and i o extracted with ethyl acetate (30 mL*3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluentethyl acetate/methanol=100/0 -> 95/5). The object fraction was concentrated under reduced pressure and dried to give 2-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-

15 pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl carbamate (83 mg) as a colorless transparent oil. 4N Hydrochloric acid/ethyl acetate solution was added to the obtained colorless transparent oil. After stirring at room temperature for 3 hrs, the resultant precipitate was collected by filtration, washed with diisopropyl ether, ethyl acetate and ice water, and dried under reduced pressure at 60°C to give the title compound (57 mg) as a pale-yellow powder. ¹H-NMR (DMSOd₆) δ 3.57 (2H, t, J= 3.0 Hz), 3.79 (2H, t, J= 3.0 Hz), 3.96 (2H, t, J= 6.0 Hz), 4.64 (2H, t, J= 6.0 Hz), 6.48 (2H, br s), 6.56 (IH, s), 7.15-7.23 (2H, m), 7.30-7.34 (2H, m), 7.41 (IH, dd, J- 3.0, 9.0 Hz), 7.47 (IH, dt, J= 6.0, 9.0 Hz), 7.63 (IH, d, J= 3.0 Hz), 7.82 (IH, s), 8.28 (IH, s), 8.56 (IH₅ S).

Production of 2-[4-({3-cWoro-4-[3-(triiluorome&yl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethanol

A mixture of 2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl benzoate (302 mg), 3- i o cUoro-4-[3-(trifluoromethyl)phenoxy]aniline (288 mg) and 1 -methyl-2-pyrrolidone (3 mL) was stirred at 120°C for 2 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected is to silica gel column chromatography (eluent, ethyl acetate:hexane=20:80 — > 100:0). The object fraction was concentrated under reduced pressure. Diethyl ether was added to the residue to allow crystallization, and dϋsopropyl ether was added, which was followed by filtration to give a white powder (286 mg). To a solution of this white powder (221 mg) in methanol (5 mL) was added IN aqueous sodium hydroxide solution (0.8 mL), and the mixture was stirred at room temperature for 2 0 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and ethyl acetate and dϋsopropyl ether were added to the obtained residue, which was followed by filtration to give the title compound (160 mg) as a white powder. 1H-NMR (CDCl₃) δ 4.16 (2H, t, J= 4.4 Hz), 4.38 (2H, t, J= 4.4 Hz), 6.12 (IH, d, J= 3.2 Hz), 6.97 (IH, d, J= 3.2 Hz), 7.09 (IH, d, J= 8.8 Hz), 7.10-7.17 (IH, m), 7.21 (IH, s), 7.32 (IH, d, J= 7.7 Hz), 7.43 (IH, t, J= 8.0 Hz), 7.52 (IH, dd, J= 8.8, 2.6 Hz), 7.84 (IH, d, J= 2.6 Hz), 8.24 (IH, s), 9.59 (IH, br s). Synthesis Example 146

Production of 2-[2-(4-{[3-cMoro-4-(3-cWorophenoxy)phenyl]ammo}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)ethoxy]ethanol

A mixture of 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-(3-chlorophenoxy)aniline (280 mg) and l-methyl-2-pyrrolidone (3 mL) was stirred at 12O⁰C for 2 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=30:70 — >^■ 100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (431 mg) in methanol (10 mL) was added IN aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 4 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (312 mg) as a white powder.

¹H-NMR (CDCl₃) δ 2.05 (IH, br s), 3.71-3.84 (4H, m), 4.03 (2H, t, J= 4.5 Hz), 4.57 (2H, t, J= 4.5 Hz), 6.61 (IH, d, J= 3.0 Hz), 6.83-6.88 (IH, m), 6.92 (IH, t, J= 2.2 Hz), 7.01-7.06 (IH, m), 7.06 (IH, d, J= 8.9 Hz), 7.19-7.27 (2H, m), 7.61 (IH, dd, J= 8.9, 2.6 Hz), 7.89 (IH, d, J= 2.6 Hz), 8.52 (IH, s), 8.82 (IH, hr s).

Production of 2-{2-[4-({3-cWoro-4-[3-(trffluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidrn-5-yl]ethoxy}ethanol A mixture of 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.037 g), 3-chloro-4-[3-(trifluoromethyl)phenoxy]anUine (863 mg) and l-methyl-2-pyrrolidone (10 mL) was stirred at 120°C for 1.5 hrs. Water and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50 -» 100:0). The object fraction was concentrated under reduced pressure. To a solution of the residue (1.420 g) in methanol (30 mL) was added IN aqueous sodium hydroxide solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced s pressure, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 -> 5:95). The object fraction was concentrated under reduced pressure. The precipitated crystals were collected by i o filtration, and washed with diethyl ether. The crude crystals were recrystallized from ethyl acetate- diisopropyl ether to give the title compound (933 mg) as a white powder. 1H-NMR (CDCl₃) δ 1.94 (IH, br s), 3.71-3.85 (4H, m), 4.03 (2H, t, J= 4.4 Hz), 4.57 (2H, t, J= 4.4 Hz), 6.63 (IH, d, J= 3.2 Hz), 7.07 (IH, d, J= 8.9 Hz), 7.08-7.14 (IH, m), 7.19 (IH, s), 7.22 (IH, d, J= 3.2 Hz), 7.31 (IH, d, J= 7.7 Hz), 7.42 (IH, t, J= 8.0 Hz), 7.63 (IH, dd, J= 8.9, 2.6 Hz), 7.91 (IH, is d, J= 2.6 Hz), 8.52 (IH, s), 8.83 (IH, br s). melting point: 130-132°C Synthesis Example 148

Production of 2-{2-[4-({3-cMoro-4-[3-(1xh^uoromethoxy)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- 0 d]pyrimidin-5-yl]ethoxy}ethanol The title compound (293 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (334 mg) and l-methyl-2-pyrrolidone (3 mL). 1H-NMR (CDCl₃) δ 1.95 (IH, br s), 3.71-3.84 (4H, m), 4.03 (2H, t, J= 4.5 Hz), 4.57 (2H, t, J= 4.5 Hz), 6.62 (IH, d, J= 3.2 Hz), 6.80-6.95 (3H, m), 7.08 (IH, d, J= 8.8 Hz), 7.21 (IH, d, J= 3.2 Hz), 7.30 (IH, t, J= 8.2 Hz), 7.62 (IH, dd, J= 8.8, 2.6 Hz), 7.90 (IH, d, J= 2.6 Hz), 8.52 (IH, s), 8.82 (IH, br s).

Production of l-{3-[2-cUoro4-({5-[2-(2-hydroxyemoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin4- yl} amino)phenoxy]phenyl} ethanone

The title compound (493 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy] ethyl benzoate (692 mg), l-[3-(4-amino-2-chlorophenoxy)phenyl]ethanone (576 mg) and l-methyl-2-pyrrolidone (5 mL).

¹H-NMR (CDCl₃) δ 1.97 (IH, br s), 2.58 (3H, s), 3.71-3.84 (4H, m), 4.03 (2H, t, J= 4.4 Hz), 4.58 (2H, t, J= 4.4 Hz), 6.63 (IH, d, J= 3.2 Hz), 7.06 (IH, d, J= 8.9 Hz), 7.15-7.20 (IH, m), 7.22 (IH, d, J= 3.2 Hz), 7.41 (IH, t, J= 7.9 Hz), 7.48-7.51 (IH, m), 7.61 (IH, dd, J= 8.9, 2.6 Hz), 7.62-7.67 (IH, m), 7.90 (IH, d, J= 2.6 Hz), 8.52 (IH, s), 8.80 (IH, br s). Synthesis Example 150

Production of l-{3-[2-cmoro^-({5-[2-(2-hydroxyetnoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4- yl}amino)phenoxy]phenyl}ethanol

5 To a solution of l-{3-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-yl}arnino)phenoxy]phenyl}ethanone (233 mg) in methanol (5 mL) was added sodium borohydride (38 mg), and the mixture was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent i o was evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (225 mg) as a white powder. 1H-NMR (CDCl₃) δ 2.47 (3H, d, J= 6.4 Hz), 3.67-3.77 (4H, m), 4.00 (2H, t, J= 4.4 Hz), 4.58 (2H, t, J= 4.4 Hz), 4.84 (IH, q, J= 6.4 Hz), 6.62 (IH, d, J= 3.3 Hz), 6.85-6.90 (IH, m), 6.96-7.00 (IH, m), 7.01-7.09 (2H, m), 7.24-7.32 (2H, m), 7.52 (IH, dd, J= 8.9, 2.6 Hz), 7.86 (IH, d, J= 2.6 Hz), 8.45

25 (IH, S).

Synthesis Example 151

Production of 2-[2-(4-{[3-cMoro-4-φyrimidin-5-yloxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethoxy]ethanol

The title compound (63 mg) was obtained as a white powder by the reaction in the same 5 manner as in Synthesis Example 146 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-cHoro-4-(pyrimidin-5-yloxy)anlline (360 mg) and 1-methyl- 2-pyrrolidone (3 mL).

¹H-NMR (CDCl₃) δ 2.08 (IH, br s), 3.72-3.84 (4H, m), 4.03 (2H, t, J= 4.4 Hz), 4.58 (2H, t, J= 4.4 Hz), 6.63 (IH, d, J= 3.1 Hz), 7.12 (IH, d, J= 8.7 Hz), 7.23 (IH₃ d, J= 3.1 Hz), 7.67 (IH, dd, J= 8.7, i o 2.6 Hz), 7.95 (IH, d, J= 2.6 Hz), 8.43 (2H, s), 8.52 (IH, s), 8.89 (IH, br s), 8.94 (IH, s). Synthesis Example 152

Production of 2-(2-{4-[(3-cWoro-4-{[2-(trifluorome1hyl)benzyl]oxy}phenyl)amino]-5H- pyrrolo[3,2-d]pyrirrύdin-5-yl}ethoxy)ethanol

15 The title compound (276 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-cHoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (277 mg), 3 -chloro-4-{[2-(trifluoromethyl)benzyl]oxy} aniline (241 mg) and l-methyl-2-pyrrolidone (3 mL).

¹H-NMR (CDCl₃) δ 2.02 (IH, br s), 3.68-3.81 (4H, m), 4.00 (2H, t, J= 4.4 Hz), 4.53 (2H, t, J- 4.4 Hz), 5.34 (2H, s), 6.58 (IH, d, J= 3.2 Hz), 6.93 (IH, d, J= 8.8 Hz), 7.17 (IH, d, J= 3.2 Hz), 7.42 (IH, 5 t, J= 7.7 Hz), 7.49 (IH, dd, J= 8.8, 2.6 Hz), 7.60 (IH, t, J= 7.7 Hz), 7.69 (IH, d, J= 7.7 Hz), 7.76 (IH, d, J= 2.6 Hz), 7.89 (IH, d, J= 7.7 Hz), 8.46 (IH, s), 8.57 (IH, br s). Synthesis Example 153

Production of 2-(2-{4-[(3-cMoro-4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)amino]-5H- i o pyrrolo[3,2-d]pyrirnidin-5-yl}ethoxy)ethanol

The title compound (393 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 146 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-cUoro4-{[3-(1rifluorome1hyl)benzyl]oxy}aniline (302 mg) and l-methyl-2-pyrrolidone (3 mL). is ¹H-NMR (CDCl₃) δ 2.03 (IH, br s), 3.68-3.80 (4H, m), 4.00 (2H, t, J= 4.4 Hz), 4.54 (2H, t, J= 4.4

Hz), 5.17 (2H, s), 6.59 (IH, d, J= 3.1 Hz), 6.95 (IH, d, J= 8.8 Hz), 7.17 (IH, d, J= 3.1 Hz), 7.48-

7.62 (3H, m), 7.66-7.76 (3H, m), 8.46 (IH, s), 8.58 (IH, br s).

Synthesis Example 154

Production of 5-[4-({3-cUoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]pentan- 1 -ol

(i) Production of 5-(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)pentyl acetate 5 A mixture of 4-cUoro-5H-pyrrolo[3,2-d]pyrirnidine (0.50 g), 5-bromopentyl acetate (0.71 mL), cesium carbonate (1.59 g) and N,N-dimethylformamide (5.0 mL) was stirred at 40⁰C for 4 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate.

The organic layer was washed with water and saturated brine and dried over magnesium sulfate.

After concentration under reduced pressure, the residue was separated and purified by silica gel i o column chromatography (eluent, ethyl acetate:hexane=l :3 — > 6:4) to give the title compound (637 mg) as a white solid.

¹H-NMR (CDCl₃) δ: 1.33-1.46 (2H, m), 1.61-1.72 (2H, m), 1.84-1.97 (2H, m), 2.04 (3H, s), 4.05

(2H, t, J= 6.6 Hz), 4.48 (2H, t, J= 7.5 Hz), 6.71 (IH, d, J= 3.3 Hz), 7.46 (IH, d, J= 3.3 Hz), 8.69 (IH, s). 15 (ϋ) Production of 5-[4-({3-cMoro-4-[3-(trffluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]pentan- 1 -ol

A solution of 5-(4-cMoro-5H-pyrrolo[3_s2-d]pyrimidin-5-yl)pentyl acetate (200 mg) and 3- cUoro-4-[3-(trifluorome1hyl)phenoxy]aniline (265 mg) in isopropyl alcohol (3.5 mL) was stirred at

80⁰C for 14 hrs. IN Aqueous sodium hydroxide solution (2.1 mL) was added at 0⁰C, and the 0 mixture was stirred at room temperature for 1 hr. IN Hydrochloric acid (2.0 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate -> ethyl acetate:methanol=l : 19) to give a colorless solid. Recrystallization from ethyl acetate-hexane gave the title compound (275 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.35 (IH, t, J= 4.7 Hz), 1.50-1.69 (4H, m), 1.92-2.05 (2H, m), 3.63-3.71 (2H, m), 4.32 (2H, t, J= 7.4 Hz), 6.59 (IH, d, J= 3.3 Hz), 6.70 (IH, s), 7.08 (IH, d, J= 8.7 Hz), 7.09-7.12 (IH, m), 7.15-7.27 (2H, m), 7.30-7.35 (IH, m), 7.40-7.43 (IH, m), 7.47 (IH, dd, J= 8.7, 2.7 Hz), 7.82 (IH, d, J= 2.7 Hz), 8.53 (IH, s).

Synthesis Example 155

Production of N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl] ethyl} -2-hydroxyacetamide (i) Production of tert-butyl [2-(4-cUoro-5H-pyrrolo[3,2-d]pyιimidin-5-yl)ethyl]carbamate

The title compound (687 mg) was obtained as a colorless solid by the reaction in the same manner as in Synthesis Example 154 (i) using 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (0.50 g), tert- butyl 2-bromoethylcarbamate (0.95 g), cesium carbonate (1.59 g) andN,N-dimethylformamide (10 ml). 1H-NMR (CDCl₃) δ: 1.31-1.46 (9H, m), 3.55 (2H, dt, J= 6.0, 6.0 Hz), 4.514.68 (3H, m), 6.74 (IH, d, J= 3.2 Hz), 7.47 (IH, d, J= 3.2 Hz), 8.71 (IH, s).

(ii) Production of tert-butyl {2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

A solution of tert-butyl [2-(4-cMoro-5H-pyrrolo[3₅2-d]pyrimidin-5-yl)ethyl]carbamate (712 5 mg) and 3-cUoro-4-[3-(trifluoromethyl)phenoxy]aniline (830 mg) in isopropyl alcohol (7.1 mL) was stirred at 80°C for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl i o acetate=l : 1 -> ethyl acetate) to give the title compound (1.12 g) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.49 (9H, s), 3.43-3.54 (2H, m), 4.434.51 (2H₅ m), 5.10 (IH, t, J= 5.6 Hz), 6.60 (IH, d, J= 3.3 Hz), 7.07 (IH, m), 7.09-7.14 (IH, m), 7.16-7.22 (2H, m), 7.25-7.30 (IH, m), 7.37-7.45 (IH, m), 7.89 (IH, dd, J= 8.7, 2.4 Hz), 8.02 (IH, d, J= 2.4 Hz), 8.50 (IH, s), 8.64 (IH, br s). is (ϋi) Production of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluorome1hyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pvrirnidm-4-amine dihydrochloride

A mixture of tert-butyl {2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)- 5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (1.12 g), 2N hydrochloric acid (15 mL) and tetrahydrofuran (30 mL) was stirred at 60°C for 20 hrs. The solvent was evaporated under reduced 0 pressure, ethanol was added, and the mixture was further concentrated. The precipitated crystals were collected by filtration and the crystals were washed with ethyl acetate to give the title compound (1.07 g) as pale-yellow crystals.

¹H-NMR (DMSOd₆) δ: 3.21-3.35 (2H, m), 4.92-5.02 (2H, m), 6.71-6.76 (IH, m), 7.24-7.32 (2H, m), 7.37 (IH, d, J= 9.0 Hz), 7.50-7.56 (IH, m), 7.64-7.71 (2H, m), 7.91-7.97 (IH, m), 7.98-8.06

(IH, m), 8.13-8.26 (3H, m), 8.71 (IH, br s), 9.88-9.99 (IH, m).

(iv) Production of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo [3,2-d]pyrimidin-5-yl] ethyl} -2-hydroxyacetamide 5 A mixture of 5-(2-aminoe1hyl)-N-{3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-arnine dihydrochloride (105 mg), glycolic acid (44 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiirnide hydrochloride (167 mg), 1-hydroxybenzotriazole monohydrate

(133 mg), triethylamine (0.40 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 3 days. Water was added to the reaction system and the mixture was extracted with i o ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -> methanol:ethyl acetate=l :9) to give the title compound (108 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.93-3.09 (IH, m), 3.59-3.73 (2H, m), 4.24 (2H, s), 4.434.53 (2H, m), 6.59 is (IH, d, J= 3.3 Hz), 7.07 (IH, d, J= 8.7 Hz), 7.09-7.46 (6H, m), 7.72 (IH, dd, J= 8.7, 2.4 Hz), 8.06

(IH, d, J= 2.4 Hz), 8.49 (IH, s), 8.57 (IH, s).

Synthesis Example 156

Production of N-{2-[4-({3-chloro-4-[3-(trifluorome1hoxy)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-(metiiylsulfonyl)acetarnide

(i) Production of tert-butyl {2-[4-({3-cMoro-4-[3-(trMuoromethoxy)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyriniidiii-5-yl]ethyl}carbamate

A solution of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate (100 mg), 3-cUoro4-[3-(trifiuoromethoxy)phenoxy]aniline (153 mg) in isopropyl alcohol (1.5 mL) was stirred at 80⁰C for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purifed by silica gel column chromatography (eluent, hexane:ethyl acetate=l : 1 — > ethyl acetate) to give the title compound (173 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.45-3.54 (2H, m), 4.43-4.52 (2H, m), 5.01-5.08 (IH, m), 6.61 (IH, d, J= 3.0 Hz), 6.80-6.95 (3H, m), 7.09 (IH, d, J= 8.7 Hz), 7.19 (IH, d, J= 3.0 Hz), 7.29-7.34 (IH, m), 7.90 (IH, dd, J= 8.7, 2.7 Hz), 8.03 (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.62 (IH, br s). (ii) Production of 5-(2-aminoetiiyl)-N-{3-cWoro-4-[3-(trifiuoromethoxy)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride

A mixture of tert-butyl {2-[4-({3-cUoro-4-[3-(trifiuoromethoxy)phenoxy]phenyl}amino)- 5H-pyiτolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (173 mg), 2N hydrochloric acid (2.5 mL) and tetrahydrofuran (5.0 mL) was stirred at 60°C for 6 hrs. Ethanol was added to the reaction system. The solvent was evaporated under reduced pressure. Ethanol was added to the concentrate, and the mixture was further concentrated under reduced pressure. The residual crystals were collected by filtration and the crystals were washed with ethyl acetate to give the title compound (155 mg) as pale-yellow crystals.

¹H-NMR (DMSO-de) δ: 3.21-3.34 (2H, m), 4.89-5.00 (2H, m), 6.74 (IH, d, J= 2.4 Hz), 6.94-7.01 (2H, m), 7.16 (IH, d, J= 8.7 Hz), 7.36 (IH, d, J= 9.0 Hz), 7.51-7.57 (IH, m), 7.62-7.69 (IH, m), 7.90-7.95 (IH, m), 7.99-8.05 (IH, m), 8.12-8.27 (3H, m), 8.71 (IH, s), 9.92 (IH, br s). (iii) Production of N-{2-[4-({3-cMoro-4-[3-(trMuorometnoxy)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyriniidin-5-yl]efhyl}-2-(meihylsulfonyl)acetamide

5 A mixture of 5-(2-aminoethyl)-N- {3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl} -5H- pyrrolo[3,2-d]pyrimidm-4-amine dihydrochloride (160 mg), 2-(methylsulfonyl)acetic acid (82.3 mg), l-ethyl-3-(3-dimethylardnopropyl)carbodiirnide hydrochloride (171 mg), 1- hydroxybenzotriazole monohydrate (137 mg), triethylamine (0.42 mL) and N₅N- dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the i o reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate — > ethyl acetate: methanol=4: 1) and crystallization from ethanol-ethyl acetate- diisopropyl ether to give the title compound (112 mg) as pale-yellow crystals. is ¹H-NMR (CDCl₃) δ: 3.12 (3H, s), 3.64-3.76 (2H, m), 3.99 (2H, s), 4.34-4.52 (2H, m), 6.62 (IH, d, J= 3.0 Hz), 6.81-6.84 (IH, m), 6.86-6.95 (2H, m), 7.08 (IH, d, J= 8.7 Hz), 7.17-7.24 (2H, m), 7.29- 7.34 (IH, m), 7.76 (IH, dd, J= 8.7, 2.7 Hz), 7.95 (IH, d, J= 2.7 Hz), 8.18 (IH, s), 8.51 (IH, s). melting point: 133-135°C Synthesis Example 157

Production of N-{2-[4-({3-cMoro-4-[3-(trffluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-methoxyacetamide

The title compound (120 mg) was obtained as colorless crystals by the reaction in the same 5 manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro4-[3-

(1iifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), methoxyacetic acid (52 mg), l-emyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (166 mg), 1-hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N- dimethylformamide (5.0 mL). i o ¹H-NMR (CDCl₃) δ: 3.44 (3H, s), 3.60-3.71 (2H, m), 4.00 (2H, s), 4.44-4.53 (2H, m), 6.62 (IH, d, J= 3.0 Hz), 7.02-7.15 (3H, m), 7.19 (IH, d, J= 3.0 Hz), 7.22-7.35 (2H, m), 7.38-7.45 (IH, m), 7.74 (IH, dd, J= 8.7, 2.4 Hz), 8.07 (IH, d, J= 2,4 Hz), 8.52 (IH, s), 8.55 (IH, s). Synthesis Example 158

5 Production of N-{2-[4-({3-cMoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3 ,2- d]pyrkmdin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide

A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (68 mg), l-e1hyl-3-(3-dimetiiylaminopropyl)carbodiimide hydrochloride (166 mg), 1- 5 hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) and N,N- dimethylformamide (5.0 mL) was stirred at room temperature for 5 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography i o (eluent, ethyl acetate -> ethyl acetate:methanol=9:l). Crystallization from ethyl acetate-dϋsopropyl ether gave the title compound (122 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 2.49 (2H, s), 2.65-2.77 (IH, m), 3.57-3.68 (2H, m), 4.44-4.53 (2H, m), 6.61 (IH, d, J= 3.0 Hz), 6.93-7.01 (IH, m), 7.07 (IH, d, J= 9.0 Hz), 7.09-7.15 (IH, m), 7.19 (IH, d, J= 3.0 Hz), 7.23-7.35 (2H, m), 7.40-7.45 (IH, m), 7.77 (IH, dd, J= 9.0, 2.7 Hz), 8.08 is (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.66 (IH, s). melting point: 167-169°C Synthesis Example 159

Production of N-{2-[4-({3-cUoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- T/US2009/058405 d]pyrimldin-5-yl]ethyl}-2-hy(-koxy-2-methylpropanamide

To a suspension of 5-(2-aniinoethyl)-N-{3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin4-amine dihydrochloride (150 mg) and triethylamine (0.40 mL) in tetrahydrofuran (5.0 mL) was added l-chlorocarbonyl-l-mefhylethyl acetate (0.12 mL) at room 5 temperature. After stirring at room temperature for 3 days, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. To a solution of the residue in ethanol (3.0 mL) was added IN aqueous sodium hydroxide solution (1.5 mL) at room temperature. After stirring at room temperature for 24 hrs, and the mixture was i o extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate — > ethyl acetate:methanol=9:l) to give the title compound (133 mg) as colorless crystals. 1H-NMR (CDCl₃) δ: 1.49 (6H, s), 2.12-2.27 (IH, m), 3.56-3.67 (2H, m), 4.42-4.52 (2H, m), 6.61 s (IH, d, J= 3.3 Hz), 7.06 (IH, d, J= 9.0 Hz), 7.08-7.14 (IH, m), 7.15-7.43 (5H, m), 7.86 (IH, dd, J= 9.0, 2.7 Hz), 8.10 (IH, d, J= 2.7 Hz), 8.51 (IH, s), 8.72 (IH, s). Synthesis Example 160

Production of N-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrύnidin-5-yl]ethyl}-2-(methylsulfonyl)acetømide

A mixture of 5-(2-aminoefhyl)-N- {3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl} -5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 2-(mefhylsulfonyl)acetic acid (79.6 mg), l-e1hyl-3-(3-dime1%lamiiiopropyl)carbodiimide hydrochloride (166 mg), 1- 5 hydroxybenzotriazole monohydrate (133 mg), triethylamine (0.40 mL) andN,N- dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography i o (eluent, ethyl acetate — » ethyl acetate:methanol=4: 1). Crystallization from ethyl acetate-dϋsopropyl ether gave the title compound (128 mg) as colorless powder crystals.

¹H-NMR (CDCl₃) δ: 3.12 (3H, s), 3.64-3.75 (2H, m), 3.98 (2H, s), 4.43-4.53 (2H, m), 6.62 (IH, d, J= 3.0 Hz), 7.07 (IH₅ d, J= 9.0 Hz)₅7.09-7.15 (IH, m), 7.18-7.33 (4H, m), 7.40-7.45 (IH, m), 7.77 (IH, dd, J- 9.0, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.19 (IH, s), 8.51 (IH, s). is melting point: 177-178⁰C Synthesis Example 161

Production of 5-[4-({3-cUoro-4-[3-(1rifiuoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]-3-methylpentane-l,3-diol 0 (i) Production of 3,5-dihydroxy-3-methylpentyl benzoate A solution of 3-methyH,3,5-pentanetriol (21.9 g), benzoic anhydride (7.39 g), pyridine (4.0 mL) and 4-(N,N-climethylamino)pyridine (0.39 g) in acetonitrile (200 mL) was stirred at room temperature for 2 days. After concentration under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexanetethyl acetate=4 : 1 -> ethyl acetate) to give the title compound (4.27 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.36 (3H, s), 1.72-1.81 (IH, m), 1.86-2.13 (3H, m), 2.47 (IH, t, J= 4.7 Hz), 2.89 (IH, s), 3.85-4.02 (2H, m), 4.52 (2H, t, J= 6.8 Hz), 7.42-7.48 (2H, m), 7.54-7.60 (IH, m), 8.00- 8.04 (2H, m).

(ϋ) Production of 5-bromo-3-hydroxy-3-methylpentyl benzoate

To a solution of 3,5-dihydroxy-3-methylpentyl benzoate (1.0 g) and carbon tetrabromide (2.78 g) in tetrahydrofuran (30 mL) was added dropwise a solution of triphenylphosphine (2.20 g) in tetrahydrofuran (10 mL) under ice-cooling. After stirring at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=9: 1 — > 6:4) to give the title compound (979 mg) as a colorless oil. 1H-NMR(CDCl₃) δ: 1.32 (3H, s), 1.78 (IH, s), 1.97-2.02 (2H, m), 2.11-2.23 (2H, m), 3.53 (2H, t, J= 8.1 Hz), 4.51 (2H, t, J= 6.5 Hz), 7.42-7.48 (2H, m), 7.55-7.60 (IH, m), 8.00-8.04 (2H, m). (iii) Production of 5-(4-cWoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3-hydroxy-3-methylpentyl benzoate

The title compound (773 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 154 (i) using 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (400 mg), 5- bromo-3-hydroxy-3-methylpentyl benzoate (979 mg), cesium carbonate (0.94 g) and N₅N- dimethylformamide (10 mL).

¹H-NMR (CDCl₃) δ: 1.41 (3H, s), 1.91 (IH, s), 2.01-2.13 (4H, m), 4.54 (2H, t, J= 6.6 Hz), 4.59-4.76 5 (2H, m), 6.71 (IH, d, J- 3.0 Hz), 7.40-7.46 (2H, m), 7.51 (IH, d, J= 3.0 Hz), 7.54-7.60 (IH, m),

7.98-8.01 (2H, m), 8.69 (IH, s).

(iv) Production of 5-[4-({3-cUoro-4-[3-(1rifluorome1h.yl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]-3-methylpentane-l,3-diol

The title compound (223 mg) was obtained as colorless crystals by the reaction in the same i o manner as in Synthesis Example 154 (ϋ) using 5-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)-3- hydroxy-3-methylpentyl benzoate (250 mg), 3-cMoro4-[3-(tπΗuorome1hyl)phenoxy]aniline (230 mg), isopropyl alcohol (1.5 mL) and IN aqueous sodium hydroxide solution (2.0 mL).

¹H-NMR (CDCl₃) δ: 1.35 (3H, s), 1.62-1.71 (IH, m), 1.89-2.22 (4H, m), 3.93-4.18 (2H, m), 4.54-

4.65 (3H, m), 6.56 (IH, d, J= 3.0 Hz), 7.04 (IH, d, J= 8.7 Hz), 7.08-7.14 (IH, m), 7.19-7.25 (2H, m), is 7.29-7.35 (IH, m), 7.39-7.44 (IH, m), 7.61 (IH, dd, J= 8.7, 2.7 Hz), 7.93 (IH, d, J= 2.7 Hz), 8.49

(lH, s), 8.52 (lH, br s).

Synthesis Example 162

Production of 2-({2-[4-({3-cMoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3 ,2- 0 d]pyrirnidin-5-yl]ethyl}thio)ethanol 2009/058405

(i) Production of 2-[(2-hydroxyethyl)thio]ethyl benzoate

A solution of 2-mercaptoethanol (1.52 mL), 2-iodoethyl benzoate (6.00 g) and ethyldnsopropylamine (4.53 mL) inN,N-dimethylformamide (60 mL) was stirred at40°C for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. 5 The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=4:l -> 3:7) to give the title compound (3.77 g) as an orange oil.

¹H-NMR (CDCl₃) δ: 2.15 (IH, t, J= 6.0 Hz), 2.83 (2H, t, J= 5.9 Hz)₃2.92 (2H, t, J= 6.8 Hz), 3.79 i o (2H, dt, J= 6.0, 6.0 Hz), 4.50 (2H, t, J= 6.8 Hz), 7.43-7.48 (2H, m), 7.55-7.61 (IH, m), 8.03-8.08

(2H, m).

(ii) Production of 2-[(2-bromoethyl)thio]ethyl benzoate

The title compound (966 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 161 (ii) using 2-[(2-hydroxyethyl)thio]ethyl benzoate (1.0 g), 15 carbon tetrabromide (2.20 g), triphenylphosphine (1.74 g) and dichloromethane (50 mL).

¹H-NMR (CDCl₃) δ: 2.95 (2H₅ t, J= 6.8 Hz), 3.02-3.08 (2H, m), 3.50-3.56 (2H, m), 4.49 (2H, t, J=

6.8 Hz)₅7.43-7.48 (2H, m), 7.55-7.61 (IH, m), 8.03-8.06 (2H, m).

(iii) Production of 2-{[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]thio}ethyl benzoate

The title compound (790 mg) was obtained as a colorless oil by the reaction in the same 0 manner as in Synthesis Example 154 (i) using 4-cUoro-5H-pyrτolo[3,2-d]pyrirnidine (420 mg), 2-

[(2-bromoethyl)thio]ethyl benzoate (966 mg), cesium carbonate (1.34 g) and N₅N- dimethylformamide (4.2 mL).

¹H-NMR (CDCl₃) δ: 2.81 (2H₅1, J= 6.8 Hz), 3.08 (2H, t, J= 6.9 Hz)₅4.45 (2H₅1, J= 6.8 Hz)₅4.69 2009/058405

(2H, t, J= 6.9 Hz), 6.73 (IH, d, J= 3.3 Hz), 7.39-7.46 (2H, m), 7.53-7.62 (2H, m), 7.96-8.06 (2H₅ m), 8.71 (IH₃ s).

(iv) Production of 2-({2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyn:olo[3,2-d]pyrimidin-5-yl]ethyl}thio)ethanol The title compound (420 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 154 (ϋ) using 2-{[2-(4-cUoro-5H-pyrrolo[3₅2-d]pyrirnidin-5- yl)ethyl]thio}ethyl benzoate (505 mg), 3-cWoro-4-[3-(trifluoromethyl)phenoxy]aniline (480 mg), isopropyl alcohol (10 mL) and IN aqueous sodium hydroxide solution (3.0 mL). 1H-NMR (CDCl₃) δ: 1.92-2.00 (IH, m), 2.52 (2H, t, J= 5.6 Hz), 3.13 (2H, t, J= 6.5 Hz), 3.65-3.75 (2H, m), 4.61 (2H, t, J= 6.5 Hz), 6.67 (IH, d, J= 3.3 Hz), 7.08 (IH₅ d, J= 8.7 Hz), 7.09-7.13 (IH₅ m), 7.18-7.23 (IH, m), 7.29 (IH₅ d, J= 3.3 Hz), 7.32-7.35 (IH, m)₅7.41-7.46 (IH₅ m), 7.51 (IH₅ dd, J= 8.7, 2.7 Hz)₅ 7.77 (IH₅ d, J= 2.7 Hz)₅ 7.80 (IH₅ s), 8.55 (IH₅ s). Synthesis Example 163

Production of N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidm-5-yl]etiiyl}-N-methyl-2-(^ (i) Production of tert-butyl [2-(4-cMoro-5H-pyrrolo[3₅2-d]pyrirnidin-5-yl)ethyl]methylcarbamate

To a solution of 2-(methylamino)ethanol (1.00 g) intetrahydrafuran (10 mL) was added di- tert-butyl dicarbonate (3.60 mL) at room temperature. After stirring at room temperature for 2 hrs, the mixture was concentrated under reduced pressure. To a solution of the residue and triethylamine (3.71 mL) intetrahydrofuran (50 mL) was added dropwise methanesulfonyl chloride (1.55 mL) at 0⁰C, and the mixture was stirred at 0⁰C for 1 hr. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give a colorless oil. The title compound (902 mg) was obtained as a pale-yellow oil by the reaction in the same manner as in Synthesis Example 154 (i) using the obtained oil, 4-chloro-5H-pyrrolo[3,2- djpyrimidine (1.34 g), cesium carbonate (5.69 g) andN,N-dimethylformamide (20 mL). 1H-NMR (CDCl₃) δ: 1.12 (4.5H, s), 1.43 (4.5H, m), 2.55 (1.5H₅ s), 2.81 (1.5H, s), 3.58-3.60 (2H, m), 4.544.69 (2H, m), 6.73 (IH, d, J= 3.0 Hz), 7.29-7.35 (0.5H, m), 7.38-7.46 (0.5H, m), 8.71 (IH, s).

(ϋ) Production of tert-butyl {2-[4-({3-cMoro-443-(1rifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo[3₅2-d]pyrimidin-5-yl]ethyl}methylcarbamate

The title compound (622 mg) was obtained as a colorless amorphous solid by the reaction in the same manner as in Synthesis Example 155 (ii) using tert-butyl [2-(4-chloro-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethyl]methylcarbamate (450 mg), 3-cUoro-4-[3-(trifluoromethyl)phenoxy]anih^vne (500 mg) and isopropyl alcohol (4.5 mL).

¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 3.01 (3H, s), 3.51-3.59 (2H, m), 4.414.51 (2H, m), 6.60 (IH, d, J= 3.0 Hz), 7.06 (IH, d, J= 8.7 Hz), 7.08-7.13 (IH, m), 7.15-7.24 (2H, m), 7.30 (IH, d, J= 8.4 Hz), 7.38-7.44 (IH, m), 7.85-7.93 (IH, m), 7.99-8.04 (IH₅ m), 8.50 (IH, s), 8.82 (IH₅ s).

(iii) Production of N-{3-cMoro4-[3-(trifluorome1hyl)phenoxy]phenyl}-5-[2-(methylamino)e1hyl]- 5H-pyrrolo[3₅2-d]pyrimidin4-amine dihydrochloride

The title compound (538 mg) was obtained as pale-yellow crystals by the reaction in the US2009/058405

same manner as in Synthesis Example 155 (iii) using tert-butyl {2-[4-({3-chloro-4-[3-

(trifluoromemyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2-d]pyrimidm-5-yl]emyl}m

(622 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).

¹H-NMR (DMSO-de) δ: 2.54 (3H, t, J= 5.3 Hz), 3.32-3.44 (2H, m), 5.01-5.15 (2H, m), 6.74 (IH, d, J= 3.3 Hz), 7.22-7.27 (2H, m), 7.36 (IH, d, J= 8.7 Hz), 7.51 (IH, d, J= 8.4 Hz), 7.60-7.69 (2H, m),

7.91-7.96 (IH, m), 8.01-8.07 (IH, m), 8.72 (IH, s), 9.00-9.18 (2H, m), 10.06 (lHbr s).

(iv) Production of N-{2-[4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirmdm-5-yl]e1hy^

The title compound (131 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3-

(1iffluorome1hyl)phenoxy]phenyl}-5-[2-(met^^ dihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (88 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (183 mg), 1-hydroxybenzotriazolemonohydrate

(146 mg), triethylamine (0.44 mL) andN,N-dimethylformamide (5.0 mL). 1H-NMR (CDCl₃) δ: 3.17 (3H, s), 3.34 (3H, s), 3.75-3.84 (2H, m), 4.18 (2H, s), 4.43-4.52 (2H, m),

6.64 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.10-7.16 (IH, m), 7.17-7.25 (2H, m), 7.32-7.37

(IH, m), 7.41-7.46 (IH, m), 7.86 (IH, dd, J= 8.7, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.46 (IH, s), 8.53

(IH₅ S).

Synthesis Example 164

Production of 2-({2-[4-({3-cMoro-4-[3-(1τifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl] ethyl} sulfinyl)ethanol

To a solution of 2-({2-[4-({3-cMoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H- 5 pyrrolo[3₅2-d]pyrimidin-5-yl]ethyl}thio)ethanol (100 nig) in dichloromethane (10 mL) was added dropwise a 70% solution of 3-chloroperbenzoic acid (58 mg) in dichloromethane (5.0 mL) at -78°C.

The mixture was stirred at -78°C for 1 hr, and aqueous sodium thiosulfate solution was added.

After stirring at room temperature for 0.5 hr, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After o concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate -» ethyl acetate:methanol^:=4:l) to give the title compound (87 mg) as colorless crystals.

¹H-NMR (DMSOd₆) δ: 2.78-3.01 (2H, m), 3.27-3.40 (IH, m), 3.42-3.58 (IH, m), 3.71-3.79 (2H, m), 4.80-4.90 (2H, m), 5.02-5.09 (IH, m), 6.58-6.63 (IH, m), 7.16-7.25 (2H, m), 7.27-7.31 (IH, m), 7.44-7.50 (IH, m), 7.59-7.64 (IH, m), 7.66-7.72 (IH, m), 7.74-7.82 (IH, m), 7.96-8.03 (IH, m),

8.37 (IH, s), 9.38 (IH, s).

Synthesis Example 165

Production of 2-({2-[4-({3-cUoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyiτolo[3,2- d]pyrimidin-5-yl]ethyl} sulfonyl)ethanol

To a solution of 2-({2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- 5 pyrrolo[3,2-d]pyrirnidin-5-yl]ethyl}thio)ethanol (150 mg), titanium tetraisopropoxide (43 μL), methanol (24 μL) and water (10 μL) in dichloromethane was stirred at room temperature for 30 min.

70% Aqueous tert-butyl hydroperoxide solution (0.12 mL) was added to the reaction system, and the mixture was stirred at room temperature for 2 days. An aqueous sodium thiosulfate solution was added to the reaction system, and the mixture was extracted with ethyl acetate. The organic i o layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography

(eluent, ethyl acetate -> ethyl acetate:methanol=4: 1) to give the title compound (118 mg) as colorless crystals.

¹H-NMR(DMSOd₆) δ: 3.09-3.15 (2H, m), 3.62-3.75 (4H, m), 4.92-5.02 (2H, m), 5.09-5.15 (IH, is m), 6.50-6.57 (IH, m), 7.16-7.32 (3H, m), 7.45-7.48 (IH, m), 7.58-7.74 (3H, m), 7.91-7.97 (IH, m),

8.37 (IH, br s), 8.69-8.79 (IH, m).

Synthesis Example 166

Production of N-{2-[4-({3-cMoro-4-[3-(1rifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3_>2- d]pyrirnidin-5-yl]e1hyl}-N-methyl-2-(methylsulfonyl)acetaim

(i) Production of tert-butyl {2-[4-({3-cMoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}arnino)-5H- 5 pyrrolo[3,2-d]pyrirmdin-5-yl]ethyl}methylcarbamate

The titie compound (665 mg) was obtained as a colorless amorphous solid by the reaction in the same manner as in Synthesis Example 155 (ii) using tert-butyl [2-(4-chloro-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethyl]methylcarbamate (463 mg), 3-chloro-4-[3-

(trifluoromethoxy)phenoxy]aniline (679 mg) and isopropyl alcohol (5.0 mL). io ¹H-NMR (CDCl₃) δ: 1.51 (9H, s), 3.01 (3H, s), 3.48-3.61 (2H, m), 4.424.50 (2H, m), 6.60 (IH, d,

J= 3.2 Hz), 6.80-6.83 (IH, m), 6.86-6.95 (2H, m), 7.08 (IH, d, J= 8.7 Hz), 7.20 (IH, d, J= 3.2 Hz),

7.28-7.33 (IH, m), 7.85-7.95 (IH, m), 7.99-8.05 (IH, m), 8.51 (IH, s), 8.81 (IH, br s).

5H-pyrrolo [3 ,2-d]pyrirnidin-4-amine dihydrochloride j 5 The titie compound (557 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 155 (iii) using tert-butyl {2-[4-({3-chloro-4-[3-

(trifluoromethoxy)phenoxy]phenyl} amino)-5H-pyrrolo [3 ,2-d]pyrimidin-5- yl]ethyl}methylcarbamate (665 mg), 2N hydrochloric acid (10 mL) and tetrahydrofuran (20 mL).

¹H-NMR (DMSO-O₆) δ: 2.52-2.66 (2H, m)), 3.29-3.45 (2H, m), 5.03-5.15 (2H, m), 6.75 (IH₅ d, J= 3.0 Hz), 6.91-7.00 (2H, m), 7.11-7.18 (IH, m), 7.35 (IH, d, J= 8.7 Hz), 7.51-7.57 (IH, m), 7.63-

7.69 (IH, m), 7.91-7.96 (IH, m), 8.06 (IH, d, J= 3.3 Hz), 8.73 (IH, s), 9.06-9.26 (2H, m), 10.11 (IH, brs).

(iii) Production of N-{2-[4-({3-cUoro-4-[3-(trifluoromefhoxy)phenoxy]phenyl}amino)-5H- 5 pyrrolo[3,2-d]pyrimidm-5-yl]ethyl}-N-met^^^

The title compound (147 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3-

(trhluoromethoxy)pheno:xy]phenyl}-5-[2-(^ amine dihydrochloride (170 mg), 2-(methylsulfonyl)acetic acid (87 mg), l-ethyl-3-(3- i o dimethylaminopropyl)carbodiirnide hydrochloride (179 mg), 1 -hydroxybenzotriazole monohydrate

(143 mg), triethylamine (0.43 mL) andN,N-dimemylformamide (5.0 ml).

¹H-NMR (CDCl₃) δ: 3.17 (3H, s), 3.34 (3H, s), 3.75-3.84 (2H, m), 4.18 (2H, s), 4.43-4.52 (2H, m),

(IH, m), 7.41-7.46 (IH, m), 7.86 (IH, d, J= 8.7, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.46 (lH,s), 8.53 15 (IH, s).

Synthesis Example 167

Production of N-{3-[4-({3-cMoro-4-[3-(trifluorome1hoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]propyl}-2-(methylsulfonyl)acetamide hydrochloride (i) Production of tert-butyl [3-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)propyl]carbamate

The title compound (1.04 g) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 154 (i) using 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), tert- butyl 3-bromopropylcarbarnate (1.00 g), cesium carbonate (1.59 g) andN,N-dimethylacetamide 5 (5.OmL).

¹H-NMR (CDCl₃) δ: 1.46 (9H, s), 2.02-2.12 (2H, m), 3.13-3.25 (2H, m), 4.50-4.66 (3H, m), 6.78

(IH₅ d, J= 3.0 Hz), 7.61-7.69 (IH, m), 8.71 (IH, s).

(ii) Production of tert-butyl {3-[4-({3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]propyl}carbamate i o The title compound (398 mg) was obtained as a colorless amorphous solid by the reaction in the same manner as in Synthesis Example 155 (ii) using tert-butyl [3-(4-chloro-5H-pyrrolo[3,2- d]pyrimidin-5-yl)propyl]carbamate (546 mg), 3-cMoro4-[3-(trifluoromethoxy)phenoxy]aniline

(640 mg) and isopropyl alcohol (10 mL).

¹H-NMR (CDCl₃) δ: 1.42 (9H_S s), 2.10-2.21 (2H, m), 3.17-3.27 (2H, m), 4.40 (2H, t, J= 7.5 Hz), _I5 4.69-4.79 (IH, m), 6.62 (IH, d, J= 3.0 Hz), 6.81 (IH, br s), 6.85-6.95 (2H, m), 7.04-7.13 (2H, m),

7.29-7.34 (2H, m), 7.54-7.60 (IH, m), 7.89 (IH, d, J= 3.0 Hz), 8.52 (IH, s).

(Hi) Production of 5-(3-ammopropyl)-N-{3-chloro4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride 20 The title compound (355 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iϋ) using tert-butyl {3-[4-({3-chloro-4-[3-

(trMuoromemoxy)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2-d]pyrirnidin-5-yl]propyl}carbam

(398 mg), 2N hydrochloric acid (10 mL) and tefrahydrofuran (20 ml). ¹H-NMR (DMSO-4) δ: 2.03-2.16 (2H, m), 2.61-2.75 (2H, m), 4.86 (2H, t, J= 6.6 Hz), 6.70 (IH, d, J= 3.0 Hz), 6.94-7.01 (2H, m), 7.11-7.19 (IH, m), 7.37 (IH, d, J= 8.7 Hz), 7.52-7.58 (IH, m), 7.67 (IH, dd, J= 8.7, 2.7 Hz), 7.95 (IH, d, J= 2.1 Hz), 7.96-815 (4H, m), 8.72 (IH, s), 9.96 (IH, br s). (iv) Production of N-{3-[4-({3-cMoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}amino)-5H- 5 pyrrolo[3,2-d]pyrimidin-5-yl]propyl}-2-(methylsulfonyl)acetarnide hydrochloride

N-{3-[4-({3-CMoro-4-[3-(trMuorome1hoxy)phenoxy]ρhenyl}arnino)-5H-pyrrolo[3,2- d]pyrirmdin-5-yl]propyl}-2-(methylsulfonyl)acetamide was obtained by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(3-aminopropyl)-N-{3-chloro-4-[3- (trrfluoromethoxy)phenoxy]phenyl} -5H~pyrrolo[3 ,2-d]pyrirnidin-4-amine dihydrochloride (170 i o mg), 2-(memylsulfonyl)acetic acid (85.0 mg), l-ethyl-3-(3-dime1hylaminopropyl)carbodiirnide hydrochloride (177 mg), 1-hydroxybenzotriazole monohydrate (141 mg), triethylamine (0.43 mL) and N,N-dimethylformamide (5.0 mL). To a solution of N-{3-[4-({3-chloro-4-[3- (1xMuoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrrmidin-5-yl]propyl}-2- (methylsulfonyl)acetamide in ethyl acetate (1.0 mL) was added 4N hydrochloric acid-ethyl acetate

15 (0.50 mL) at room temperature, and the mixture was stirred at room temperature for 1 hr. After concentration under reduced pressure, dϋsopropyl ether was added, and the precipitated crystals were collected by filtration. The crystals were washed with dϋsopropyl ether to give the title compound (128 mg) as colorless powder crystals. 1H-NMR (DMSOd₆) δ: 1.88-2.00 (2H, m), 2.97-3.08 (2H, m), 3.11 (3H, s), 4.04 (2H, s), 4.63-4.72 0 (2H, m), 6.67 (IH, d, J= 3.0 Hz), 6.94-7.01 (2H, m), 7.13-7.21 (IH, m), 7.36 (IH, d, J= 9.0 Hz), 7.49-7.65 (2H, m), 7.91 (IH, d, J= 2.4 Hz), 7.96 (IH, d, J= 3.0 Hz), 8.45-8.52 (IH, m), 8.70 (IH, s), 9.67 (lH, br s).

Synthesis Example 168

Production of N-{2-[4-({3-cMoro-4-[3-(Mfluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyriirύdin-5-yl]e1iiyl}-3-(metiiylsulfonyl)propanamide

To a mixture of 5-(2-arriinoe1hyl)-N-{3-cMoro-4-[3-(trffluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-arnine dihydrochloride (230 mg) andtriethylamine (0.61 mL) in tetrahydrofuran (8.0 mL) was added 3-(methylthio)propionyl chloride (0.15 mL) under ice-cooling.

After stirring at room temperature for 20 hrs, water was added, and the mixture was extracted with i o ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate — > ethyl acetate:methanol=9: 1) to give the title compound (133 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 2.13(3H, s), 2.59 (2H, t, J= 6.9 Hz), 2.83 (2H, t, J= 6.9 Hz), 3.57-3.69 (2H, m), ₁₅ 4.454.55 (2H, m), 6.39-6.47 (IH, m), 6.62 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.09-7.14

(IH, m), 7.20 (IH, d, J= 3.0 Hz)₅7.23-7.27 (IH, m), 7.29-7.34 (IH, m), 7.39-7.47 (IH, m), 7.83 (IH, dd, J= 8.7, 2.7 Hz), 8.12 (IH, d, J= 2.7 Hz), 8.523 (IH, s), 8.63 (IH, s).

(ii) Production of N-{2-[4-({3-cMoro4-[3-(trffluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo [3 ,2-d]pyrimidin-5-yl] ethyl} -3 -(methylsuhOnyl)propanamide The title compound (97 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 165 using N-{2-[4-({3-chloro-4-[3- (1riiluoromethyl)phenoxy]phenyl}amm

(methylthio)propanamide (150 mg), titanium tetraisopropoxide (40.3 μL), methanol (22.2 μL), 5 water (9.3μL), 70% aqueous tert-butyl hydroperoxide solution (0.12 mL) and dichloromethane (8.0 mL).

¹H-NMR (DMSOd₆) δ: 2.41-2.57 (2H, m), 2.95 (3H₅ s), 3.26 (2H, t, J= 7.5 Hz), 3.35-3.45 (2H, m), 4.484.58 (2H, m), 6.51 (IH, d, J- 3.0 Hz), 7.18-7.32 (3H, m), 7.43-7.50 (IH, m), 7.58-7.67 (2H, m), 7.73-7.82 (IH, m), 8.02-8.07 (IH, m), 8.34-8.45 (2H, m), 8.75 (IH, s). i o Synthesis Example 169

Production of N-{2-[4-({3-cMoro-4-[3-(Mfluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirrύdm-5-yl]emyl}-2-methyl-2-(methylsuh^conyl)propariamide

To a solution of 2-methyl-2-(methylsuh^conyl)propanoic acid (115 mg) and N₅N- 5 dimethylformamide (catalytic amount) in tetrahydrofuran (5.0 mL) was added thionyl chloride (0.10 mL) at room temperature. After stirring at room temperature for 3 hrs, the mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran (10 mL) was added dropwise to a suspension of 5-(2-aminoethyl)-N-{3-chloro4-[3- (trifluorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3₅2-d]pyrimidin-4-amine dihydrochloride (180 mg) and triethylamine (0.48 mL) in tetrahydrofuran (10 mL) at room temperature. After stirring at room temperature for 20 hrs, water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -» ethyl acetate:rnethanol=9: 1) to give the title compound (205 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.70 (6H, s), 2.93 (3H, s), 3.63-3.73 (2H, m), 4.43-4.52 (2H, m), 6.64 (IH, d, J= 3.3 Hz), 7.09 (IH, d, J= 8.7 Hz), 7.10-7.16 (IH, m), 7.18-7.24 (2H, m), 7.27-7.35 (2H, m), 7.40- 7.47 (IH, m), 7.90 (IH, dd, J= 8.7, 2.7 Hz), 8.05 (IH, d, J= 2.7 Hz), 8.38 (IH, s), 8.54 (IH, s). melting point: 167-168°C Synthesis Example 170

Production of N-{2-[4-({3-cUoro-4-[3-(Mfluoromemoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]ρyrimidm-5-yl]ethyl}-2-methyl-2-(memylsuhOnyl)propanamide

To a solution of 2-methyl-2-(methylsulfonyl)propanoic acid (92 mg) and N₃N- dimethylformamide (catalytic amount) in tetrahydrofuran (5.0 mL) was added thionyl chloride (80 μL) at room temperature. After stirring at room temperature for 3 hrs, the mixture was concentrated under reduced pressure. A solution of the residue in tetrahydrofuran-dichloromethane (10 mL-10 mL) was added dropwise to a suspension of 5-(2-aminoethyl)-N-{3-chloro-4-[3- (ttifluoromethoxy)phenoxy]phen^ mg) and triethylamine (0.39 mL) in tetrahydrofiiran (10 mL) at room temperature. After stirring at room temperature for 20 hrs, aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -» ethyl acetate:methanol=9: 1) to give the title compound (108 mg) as pale-yellow crystals. 1H-NMR (CDCl₃) δ: 1.70 (6H, s), 2.93 (3H₅ s), 3.62-3.73 (2H, m), 4.42-4.51 (2H, m), 6.64 (IH, d, J= 3.3 Hz), 6.82-6.86 (IH, m), 6.88-6.96 (2H, m), 7.09 (IH, d, J= 9.0 Hz), 7.21 (IH, d, J= 3.3 Hz), 7.26-7.35 (2H, m), 7.89 (IH, dd, J= 9.0, 2.6 Hz), 8.04 (IH, d, J= 2.6 Hz), 8.37 (IH, s), 8.54 (IH, s). Synthesis Example 171

Production of N-{3-cMoro^-[3-(Mfluoromethyl)phenoxy]phenyl}-5-[2-(2-methoxyethoxy)ethyl]- 5H-pyrrolo[3,2-d]pyrirnidin-4-amine hydrochloride

4-Ctøoro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) was dissolved in N₅N-dimethylformamide (10 mL), and potassium carbonate (830 mg) and 2-(2-methoxyethoxy)ethyl 4- methylbenzenesuhxinate (920 mg) were added and the mixture was stirred at room temperature for 12 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice- cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate^SOrSO — >• 0:100). The obtained oil was dissolved in isopropyl alcohol (10 mL), and 3-cWoro4-[3-(trifluoromethyl)phenoxy]aniline was added. The mixture was stirred at 90°C for 4 hrs, saturated aqueous sodium hydrogen carbonate was added to 5 the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > ethyl acetate:methanol=90:10), and crystallized from 4N hydrochloric acid-ethyl acetate solution/hexane to give the title compound (277 mg). i o ¹H-NMR(DMSO-^) δ: 3.06 (3H, s), 3.33 - 3.35 (2H, m), 3.55 - 3.61 (2H, m), 3.83 - 3.86 (2H, m), 4.83 - 4.86 (2H, m), 6.71 (IH, d, J= 3 Hz), 7.24 - 7.72 (7H, m), 7.99 - 8.04 (2H, m), 8.77 (IH, s), 9.92 (IH, s). Synthesis Example 172

5 Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (methylsuh°onyl)e1hoxy]emyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine © Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (methyliMo)e1hoxy]e1hyl}-5H-pyrrolo[3,2-d]pyrirrddin4-arnirie

The compound (150 mg) of Synthesis Example 147 was dissolved in tetrahydrofuran (10 mL) and triethylamine (1.50 mL) and methanesulfonyl chloride (0.70 mL) were added under ice- cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to this reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a 5 mixed solvent of N,N-dimethylformamide (5.0 mL) and tetrahydrofuran (4.0 mL). Sodium methanethiolate (180 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, i o ethyl acetate:methanol=100:0 ~-> ethyl acetate:methanol=90:10) to give the title compound (123 mg).

¹H-NMR(CDCl₃) δ: 2.02 (3H, s), 2.66 - 2.73 (2H, m), 3.74 - 3.78 (2H, m), 3.98 - 4.01 (2H, m), 4.55 - 4.58(2H, m), 6.66 (IH, d, J= 3 Hz), 7.07 - 7.63 (6H, m), 7.88(1H, br s), 8.02 (IH, s), 8.55 (IH, s), 8.74(1H, s).

15 (ii) Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2- (me1hylsuh^conyl)ethoxy]e1hyl}-5H-pyrrolo[3,2-d]pyrirrύdin-4-amine

N-{3-CMoro-4-[3-(trifluorome%l)phenoxy]phenyl}-5-{2-[2-(methylthio)ethoxy]ethyl}- 5H-pyrrolo[3,2-d]pyrirnidin-4-arnine (70.0 mg) was dissolved in dichloromethane (5.0 mL), titanium tetraisopropoxide (0.10 mL), methanol (0.50 mL) and 70% aqueous tert-butyl 0 hydroperoxide solution (8.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture under ice- cooling, and the mixture was stirred at room temperature for 1 hr and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» ethyl acetate:methanol=90:10). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (62.5 mg).

¹H-NMR (CDCl₃) δ: 2.62 (3H, s), 4.57 - 4.61 (2H, m), 6.68 (IH, d, J= 3 Hz), 4.16 (IH, m), 5.08 5 (2H, s), 5.55 (2H, s), 6.33 (IH, br s), 6.66 (IH, d, J= 3 Hz), 7.09 - 7.60 (7H, m), 7.86 (IH, d, J= 3 Hz), 8.11 (lH, s), 8.55 (lH, s). Synthesis Example 173

Production ofN-{3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-(2,2,2- i o ttifluoroemoxy)ethoxy]e1hyl}-5H-pyrrolo[3,2-d]pyrirrύdin-4-amm hydrochloride

The title compound (107 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 172 (i) using the compound (200 mg) of Synthesis Example 147, sodium

2,2,2-trifluoroethanolate (1.20 g), tetrahydrofuran (7.0 mL) andN,N-dimethylformamide (10 mL) at a reaction temperature of 50⁰C₃ and crystallization from 4N hydrochloric acid-ethyl acetate 15 solution/hexane.

¹H-NMR (DMSOd₆) δ: 3.09 (4H, m), 3.30-3.39 (2H₃ m), 4.61 (2H, br s), 5.12 (2H₃ br s), 6.53 (IH₃ d, J= 3 Hz)₃7.20-8.56 (10H₃ m).

Synthesis Example 174

Production of 2-(methylsulfoήyl)ethyl {2-[4-({3-chloro-4-[3- (frifluoromethyl)phenoxy]phenyl}amino)-5H-^^

5-(2-Aminoe1hyl)-N-{3-cWoro4-[3-(Mfluorometh^^^

5 d]pyrimidin-4-amine dihydrochloride (64.1 mg) and triefhylamine (1.0 mL) were dissolved in dichloromethane (5.0 mL), l-({[2-(methylsulfonyl)ethoxy]carbonyl}oxy)pyrrolidine-2,5-dione (45.6 mg) was added, and the mixture was stirred at room temperature for 2 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, i o and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > ethyl acetate:methanol=95:5). Crystallization from diethyl ether/hexane gave the title compound (61.0 mg).

¹H-NMR(CDCl₃) δ: 3.10 (3H, s), 3.48-3.52 (2H, m), 3.70-3.75 (2H₅ m), 4.62-4.68 (2H, m), 4.75- 4.79 (2H, m), 5.57 (lH,m), 6.78 (IH, d, J= 3 Hz), 7.22-7.61 (6H, m), 7.92 (IH, m), 8.11 (IH, m), is 8.20 (IH, s), 8.68 (IH, s). Synthesis Example 175

Production of N-{2-[4-({3-cMoro4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-N'-[2-(me1hylsulfonyl)ethyl]urea

5-(2-Aminoe1hyl)-N-{3-cWoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3,2- 5 d]pyrknidin-4-amine dihydrochloride (54.1 mg) and triefhylamine (0.7 mL) were dissolved in dichloromethane (10 mL), 1 , 1 '-carbonylbis(lH-imidazole) was added, and the mixture was stirred at room temperature. After 1 hr, 2-(methylsulfonyl)ethanamine (1.0 mL) was added, and the mixture was further stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with dichloromethane. The i o extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > ethyl acetate:methanol=90:10). crystallized from diethyl ether/ethyl acetate/hexane to give the title compound (37.6 mg). 1H-NMR (CDCl₃) δ: 2.84 (3H, s), 3.11-3.17 (2H, m), 3.40-3.50 (2H, m), 3.66-3.72 (2H, m), 4.39-

15 4.44 (2H, m), 5.55 (2H,m), 6.47 (IH, d, J= 3 Hz), 7.00-7.39 (6H, m), 7.81-7.88 (IH, m), 7.99 (IH, m), 8.40 (IH, s), 8.73 (IH, s). Synthesis Example 176

Production of 5-{2-[2-(tert-butylsulfonyl)ethoxy]ethyl}-N-{3-cMoro-4-[3- (1riiluoromethyl)phenoxy]phenyl}-5H-py^

(i) Production of 5-{2-[2-(tert-butylthio)ethoxy]ethyl}-N-{3-chloro-4-[3- (trifluorome1hyl)phenoxy]phenyl}-5H-pyπ-olo[3,2-d]pyrimidin4-amine

2-{2-[4-({3-CMoro4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethoxy}ethanol (150 mg) was dissolved intetrahydrofuran (6.0 mL), and triefhylamine (1.00 mL) and methanesulfonyl chloride (0.59 mL) were added under ice-cooling and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to this reaction solution under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent of N,N-dmethylformamide (4.0 mL) and tetrahydrofuran (6.0 mL). Sodium 2- methylρropane-2-thiolate (220 mg) was added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice- cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» ethyl acetate:methanol^:=90:10) to give the title compound (143 mg). 1H-NMR (CDCl₃) δ: 1.23 (9H, s), 2.69-2.73 (2H, m), 3.73-3.78 (2H, m), 3.97-3.99 (2H, m), 4.54- 4.57 (2H, m), 6.66 (IH, d, J= 3 Hz), 7.07-7.45 (6H, m), 7.64-7.68 (IH, m), 7.89 (IH, d, J= 3 Hz), 8.55 (IH, s), 8.77 (IH, s).

(ϋ) Production of 5-{2-[2-(tert-butylsulfonyl)ethoxy]efhyl}-N-{3-chloro4-[3- (1riiluorome1iiyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyriinidin4-amine 5 5-{2-[2-(tert-ButyltMo)ethoxy]e^

5H-pyrrolo[3,2-d]pyrimidin-4-amJne (140 mg) was dissolved in dichloromethane (5.0 mL), titanium tetraisopropoxide (0.90 mL), methanol (0.20 mL) and 70% aqueous tert-butyl hydroperoxide solution (7.0 mL) were added, and the mixture was stirred at room temperature for 1 hr. Saturated aqueous sodium thiosulfate solution was added to the reaction mixture under ice- i o cooling, and the mixture was stirred at room temperature for 1 hr and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:methanol=90:10). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (10.6 mg). is ¹H-NMR (CDCl₃) δ: 1.24 (9H, s), 3.00-3.04 (2H, m), 3.97-4.08 (4H, m), 4.49-4.52 (2H, m), 6.59 (IH, d, J= 3 Hz), 7.00-7.56 (7H, m), 7.84 (IH, d, J= 3 Hz), 8.27 (IH, s), 8.48 (IH, s). melting point: 79.5-81.5°C Synthesis Example 177

Production of N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-{2-[2-

(phenylsulfonyl)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrinddin-4-amm

The title compound (96.4 mg) was obtained by the reaction in the same manner as in

Synthesis Example 172 (i) using the compound (100 mg) of Synthesis Example 147, sodium benzenethiolate (200 mg), tetrahydrofuran (5.0 mL) andN,N-dimethyUOrmamide (4.0 mL).

¹H-NMR (CDCl₃) δ: 3.06-3.10 (2H, m), 3.75-3.79 (2H, m), 3.94-3.97 (2H, m), 4.52-4.55 (2H, m), 6.66 (IH, d, J= 3 Hz), 7.01-7.56 (12H, m), 7.88 (IH, d, J= 3 Hz), 8.56(1H, s), 8.71 (IH, s).

(ii) Production of N-{3-chloro-4-[3-(trifiuoromethyl)phenoxy]phenyl}-5-{2-[2-

(phenylsuh°onyl)emoxy]e1hyl}-5H-pyrrolo[3₃2-d]pyrirrύdin4-aπiine

The title compound (7.2 mg) was obtained by the reaction in the same manner as in

Synthesis Example 172 (ii) using N-{3-chloro4-[3-(trifiuoromethyl)phenoxy]phenyl}-5-{2-[2- (phenylthio)ethoxy]e1hyl}-5H-pyrrolo[3,2-d]pyrirrddin4-arnine (60 mg), dichloromethane (5.0 mL), N,N-dimemylformamide (2.0 mL), titanium tetraisopropoxide (0.90 mL), methanol (0.20 mL) and 70% aqueous tert-butyl hydroperoxide solution (4.0 mL).

¹H-NMR (CDCl₃) δ: 3.23-3.27 (2H, m), 3.88-4.00 (4H, m), 4.42-4.45 (2H, m), 6.58 (IH, d, J= 3 Hz), 7.00-7.70 (12H, m), 7.79 (IH, d, J= 3 Hz), 8.13 (IH, s), 8.47 (IH, s).

Synthesis Example 178

Production of 2-[(2-{2-[4-({3-cUoro4-[3-(ttifluoromethyl)phenoxy]phenyl}ainino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy} ethyl)sulfinyl]efhanol

The compound (120 mg) obtained by the reaction in the same manner as in Synthesis Example 172 (i) using the compound (200 mg) of Synthesis Example 147, sodium 2- hydroxyethanethiolate (2.02 g), tetrahydrofuran (6.0 mL) andN,N-dimethylformamide (5.0 mL) was dissolved in dichloromethane (7.0 mL). m-Chloroperbenzoic acid (110 mg) was added at - 18°C and the mixture was stirred for 5 hrs. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate/hexane gave the title compound (97.0 mg).

¹H-NMR (CDCl₃) δ: 2.66 - 2.73 (2H, m), 2.90-2.98 (2H, m), 3.93-4.13 (6H, m), 4.56-4.62 (2H, m), 6.68 (IH, d, J= 3 Hz), 7.08-7.59 (7H,m), 7.83 (IH, d, J= 3 Hz), 8.37 (IH, m), 8.55 (IH, s). Synthesis Example 179

Production of 2-[(2-{2-[4-({3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirrddin-5-yl]ethoxy}e1hyl)sulfonyl]ethanol

The title compound (60.2 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 172 (ϋ) using the compound (87.0 mg) of Synthesis Example 178, dichloromethane (4.0 mL), N^Sf-dimethylformamide (2.0 mL), titanium tetraisopropoxide (0.90 mL), methanol (0.50 mL) and 70% aqueous tert-butyl hydroperoxide solution (5.0 mL). 1H-NMR (CDCl₃) δ: 2.78-2.82 (2H, m), 3.34-3.38 (2H, m), 3.79 (2H, m), 4.03-4.13 (4H, m), 4.57- 4.60 (2H, m), 6.68 (IH, d, J= 3 Hz), 7.07-7.57 (7H, m), 7.80 (IH, d, J= 3 Hz), 8.23 (IH, m), 8.54 (IH, s).

Synthesis Example 180

Production of N-{2-[4-({3-cWoro-4-[3-(trMuorome1byl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethyl} - 1 -(methylsutfonytymethanesulfonamide

5-(2-Aminoemyl)-N-{3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2- d]pyrirnidin-4-amine dihydrochloride (245 mg) andN-methylmorpholine (1.0 mL) were dissolved in dichloromethane (6.0 mL), (methylsulfonyl)methanesulfonyl chloride (0.40 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Saturated aqueous sodium hydrogen carbonate was added under ice-cooling, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue 5 was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate to give the title compound (79.4 mg) as crystals.

¹H-NMR (CDCl₃) δ: 3.60 (3H, br s), 3.83-3.92 (4H, m), 4.82 (2H, br s), 6.68 (IH, d, J= 3 Hz)₃7.24- 7.99 (8H, m), 8.73 (IH, s), 8.73 (IH, s), 9.72 (IH, s). i o Synthesis Example 181

Production of 3-[2-chloro-4-(6,7-dihydro-9H-pyrirnido[4',5 ' :4,5]pyrrolo[2,l -c] [1 ,4]oxazin-4- ylamino)phenoxy]benzonitrile hydrochloride

(i) Production of 4-phenoxy-6,7-dihydro-9H-pyrirnido[4',5' :4,5]pyrrolo[2, 1 -c] [1 ,4]oxazine 5 The compound (130 mg) obtained in Synthesis Example 21 (ϋ) was dissolved inN,N- dimethylformamide (2.16 mL), and cesium carbonate (1.05 g) and 1,2-dibromoethane (0.255 mL) were sequentially added. The mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (30 mL), and washed with water (20 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue0 was dissolved in N,N-dimethylformamide (1.08 mL), potassium t-butoxide (90.5 mg) was added, and the mixture was stirred at room temperature for 1 hr. Ethyl acetate (30 mL)/water (20 mL) was added, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 -> 0/100) to give the title compound (76 mg).

5 ¹H-NMR (CDCl₃) δ 4.20 (2H, t, J= 5 Hz), 4.55 (2H, t, J= 5 Hz), 5.06 (2H, s), 6.40 (IH, s), 7.2-7.5 (5H, m), 8.44 (lH, s).

(ϋ) Production of 3-[2-chloro4-(6,7-dihydro-9H-pyrimido[4',5 ' :4,5]pyrrolo[2,l -c] [1 ,4]oxazin-4- ylamjno)phenoxy]benzonitrile hydrochloride

A rrmctøe of 4-phenoxy-6,7-dihycko-9H-pyr^ i o mg), 3 -(4-amino-2-chlorophenoxy)benzonitrile (95 mg), pyridine hydrochloride (75 mg) and 1 - methyl-2-pyrrolidone (1 mL) was stirred at 14O⁰C for 14 hrs. After the completion of the reaction, the mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and saturated brine. The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column

15 chromatography (hexane/ethyl acetate=50/50 -» 0/100). The obtained fractions were collected and concentrated, and the residue was dissolved in ethyl acetate (2 mL) and treated with 4N hydrochloric acid/ethyl acetate (0.13 mL) to give the title compound (81 mg) as hydrochloride crystals. 1H-NMR (DMSO-d_δ) δ 4.17 (2H, t, J= 5 Hz), 4.75 (2H, m), 5.07 (2H, s), 6.55 (IH, s), 7.2-7.7 (6H, 0 m), 7.94 (IH, m), 8.70 (IH, s), 9.91 (IH, br s). Synthesis Example 182

Production of N-{3-chloro-4-[3-(trifluoromefhyl)phenoxy]phenyl}-5-(2-{[2- (memylsdfonyl)ethyl]ainino}ethyl)-5H-pyro^

(i) Production of 4-cMoro-5-(2,2-die1iioxyethyl)-5H-pyrrolo[3,2-d]pyrirnidine 5 4-CUoro-5H-pyrrolo[3,2-d]pyrirnidine (1 g) was dissolved in N,N-dirnethylformarnide (13 mL), cesium carbonate (6.37 g) and 2-bromo-l,l-diethoxyethane (2.94 mL) were sequentially added and the mixture was stirred at 80°C for 4.5 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel i o column chromatography (hexane/ethyl acetate=50/50 -> 0/100) to give the title compound (1.26 g) as a yellow oil.

¹H-NMR (CDCl₃) δ 1.14 (6H, t, J= 6 Hz), 3.40 (2H, m), 3.72 (2H, m), 4.08 (IH, m), 4.56 (2H, d, J= 5 Hz), 6.71 (IH, d, J= 3 Hz), 7.55 (IH, d, J= 3 Hz), 8.69 (IH, s). (ii) Production of 4-phenoxy-5-(2,2-diemoxyemyl)-5H-pyrrolo[3,2-d]pyrimidine is A mixture of 4-cUoro-5-(2,2-diethoxye1hyl)-5H-pyrrolo[3,2-d]pyrirnidine (1 g), phenol

(420 mg), potassium carbonate (617 mg) and l-methyl-2-pyrrolidone (6.74 mL) was stirred with heating at 140°C for 6 hrs. The reaction mixture was diluted with ethyl acetate (100 mL), and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography 0 (hexane/ethyl acetate=90/10 -» 40/60) to give the title compound (1.15 g) as a yellow oil. ¹H-NMR (CDCl₃) δ 1.13 (6H, t, J= 7 Hz), 3.40 (2H, m), 3.69 (2H, m), 4.51 (2H, d, J= 6 Hz), 4.76

(IH, t, J= 6 Hz), 6.65 (IH, d, J= 3 Hz), 7.2 - 7.5 (6H, m), 8.45 (IH, s).

(iii) Production of 2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethane-l,l-diol

4-Phenoxy-5-(2,2-diethoxye1hyl)-5H-pyrrolo[3,2-d]pyrinτidine (1.1 g) was dissolved in dichloromethane (4.53 mL)/trifluoroacetic acid (4.53 mL), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The mixture was washed with saturated aqueous sodium hydrogen carbonate (80 mL), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (826 mg) as a white solid. 1H-NMR (DMSOd₆) δ 4.35 (2H, d, J= 6 Hz), 5.17 (IH, t, J= 6 Hz), 6.14 (2H, d, J= 6 Hz), 6.59 (IH, d, J= 3 Hz), 7.2-7.6 (5H, m), 7.75 (IH, d, J= 3 Hz), 8.28 (IH, s). (iv) Production of 2-(methylsuh^conyl)-N-[2-(4-phenoxy-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethyl]ethanamine

2-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrirmdin-5-yl)ethane-l,l-diol (500 mg) and2- (methylsulfonyl)ethylamine (341 mg) were dissolved in N,N-dimethylformamide (29 mL)/acetic acid (2.9 mL), and the mixture was stirred at room temperature for 1.5 hrs. Sodium triacetoxyborohydride (579 mg) was added, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 -» 70/30) to give the title compound (508 mg) as a candy-like substance.

¹H-NMR (CDCl₃) δ 2.84 (3H, s), 3.0-3.2 (6H, m), 4.54 (2H, t, J= 6 Hz), 6.66 (IH, d, J= 3 Hz), 7.2- 7.5 (6H, m), 8.45 (lH, s).

(v) Production of N- {3 -chloro-4- [3 -(trifluoromethyl)phenoxy]phenyl} -5-(2- { [2- (memylsulfonyl)emyl]amino}ethyl)-5H-pyrroto^

2-(Methylsulfonyl)-N-[2-(4-phenoxy-5H-pyrro^

(500 mg) was dissolved in tetrahydrofuran (5 mL), and di-tert-butyl dicarbonate (0.478 mL) and triethylamine (0.29 mL) were added, and the mixture was stirred at room temperature for 3 hrs. The 5 reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 -» 0/100). A mixture of a portion (243 mg) taken from the obtained residue (491 mg), 3-cWoro4-[3-(tifluoromethyl)phenoxy]aniline (228 mg), pyridine hydrochloride (183 mg) and phenol (406 mg) was stirred at 140°C for 14 hrs. After the completion of the reaction, the mixture was diluted with dichloromethane (50 mL) and washed with i o saturated aqueous sodium hydrogen carbonate (30 mL). The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate/methanol=100/0 — > 70/30) and crystallized from diisopropyl ether to give the title compound (123 mg). 1H-NMR (DMSOd₆) δ 2.88 (3H, s), 2.89 (2H, m), 2.99 (2H, m), 3.16 (2H, t, J= 6 Hz), 4.50 (2H, is m), 6.51 (IH, d, J= 3 Hz), 7.22 (2H, m), 7.31 (IH, d, J= 9 Hz), 7.46 (IH, d, J= 8 Hz), 7.5-7.7 (3H, m), 8.04 (IH, d, J= 2 Hz), 8.35 (IH, s).

Synthesis Example 183

Production of 2-[2-(4-{[4-[(6-methylpyridin-3-yl)oxy]-3-(trMuoromethyl)phenyl]amino}-5H- pyiτolo[3,2-d]pyriinidin-5-yl)ethoxy]efhatiol

A mixture of 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (150 mg), 4-[(6-methylpyridin-3-yl)oxy]-3-(trMuoromethyl)aniline (175 mg) and l-methyl-2- pyrrolidone (0.863 mL) was stirred with heating at 14O⁰C for 2.5 hrs. The reaction mixture was 5 diluted with ethyl acetate (80 mL) and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0 -> 90/10). The object fraction was concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.9 mL), IN sodium hydroxide (0.433 mL) was i o added, and the mixture was stirred at room temperature for 1.5 hrs. IN hydrochloric acid (0.433 mL) was added, and the mixture was diluted with ethyl acetate (80 mL) and washed with saturated brine (30 mL). The organic layer was dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (ethyl acetate/methanol=100/0 -> 90/10) and crystallized from dϋsopropyl ether to give the title

15 compound (118 mg).

¹H-NMR (DMSOd₆) δ 2.46 (3H, s), 3.47 (4H, br s), 3.82 (2H, m), 4.66 (3H, m), 6.51 (IH, d, J= 3 Hz), 7.10 (IH, d, J= 9 Hz), 7.31 (2H, m), 7.68 (IH, d, J= 3 Hz), 7.90 (IH, dd, J= 3 Hz, 9 Hz), 8.10 (IH, d, J= 3 Hz), 8.24 (IH, d, J= 3 Hz), 8.30 (IH, s), 8.99 (IH, br s). Synthesis Example 184

Production of 2-(4-{[3-cUoro-4-(3-cMorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethanol

The title compound (81 mg) was obtained as colorless crystals by the reaction in the same 5 manner as in Synthesis Example 183 using 2-(4-cMoro-5H-pyirolo[3,2-d]pyrimidin-5-yl)ethyl benzoate (100 mg), 3-chloro4-(3-chlorophenoxy)aniline (126 mg) and l-methyl-2-pyrrolidone (0.66 mL).

¹H-NMR (DMSO-d_δ) δ 3.87 (2H, m), 4.53 (2H, t, J- 4.5 Hz), 6.31 (IH, br s), 6.51 (IH, d, J= 3 Hz), 6.88 (IH, d, J= 9 Hz), 6.95 (IH, s), 7.15 (IH, d, J= 9 Hz), 7.28 (IH, d, J= 9 Hz), 7.38 (IH, t, J= 9 i o Hz), 7.60 (IH, dd, J= 2 Hz, 9 Hz), 7.66 (IH, d, J= 3 Hz), 7.97 (IH, d, J= 2 Hz), 8.34 (IH, s), 9.89 (lH, br s). Synthesis Example 185

Production of 2-{2-[4-({3-me1hoxy4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- 15 d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (80 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-me1hoxy-4-[3-(trifluorome1hyl)phenoxy]aniline (185 mg) and l-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-dβ) δ 3.52 (4H, m), 3.74 (3H, s), 3.85 (2H, t, J= 5 Hz), 4.65 (2H, t, J= 5 Hz), 4.76 5 (IH, 1, J= 5 Hz), 6.51 (IH, d, J= 3 Hz), 7.13 (3H, m), 7.35 (2H, m), 7.49 (IH, d, J= 2 Hz), 7.55 (IH, t, J= 8 Hz), 7.68 (IH, d, J= 3 Hz), 8.32 (IH, s), 8.90 (IH, br s). Synthesis Example 186

Production of 2-{2-[4-({3-(hydroxyme1hyl)-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H- o pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethanol

The title compound (175 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), {5-amino-2-[3-(trifluoromethyl)phenoxy]phenyl}methanol

(184 mg) and l-methyl-2-pyrrolidone (0.863 mL). s ¹H-NMR (DMSOd₆) δ 3.52 (4H, m), 3.74 (3H, s), 3.85 (2H, t, J= 5 Hz), 4.65 (2H, t, J= 5 Hz), 4.76

(IH, t, J= 5 Hz), 6.51 (IH, d, J= 3 Hz), 7.13 (3H, m), 7.35 (2H, m), 7.49 (IH, d, J= 2 Hz), 7.55 (IH₅ t, J= 8 Hz), 7.68 (IH, d, J= 3 Hz), 8.32 (IH, s), 8.90 (IH, br s).

Synthesis Example 187

Production of 2-{2-[4-({3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-ρyπ:olo[3,2- d]pyrimidin-5-yl]ethoxy}ethanol

The titie compound (98 mg) was obtained as colorless crystals by the reaction in the same 5 manner as in Synthesis Example 183 using 2-[2-(4-cHoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methyl-4-[3-(trifluoromemyl)phenoxy]ariiline (174 mg) and l-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSOd₆) δ 2.13 (3H, s), 3.51 (4H, m), 3.84 (2H, t, J= 4.5 Hz), 4.63 (2H, t, J= 4.5 Hz), 4.74 (IH, t, J= 4.5 Hz), 6.49 (IH, d, J= 3 Hz), 7.04 (IH, d, J= 9 Hz), 7.16 (2H, m), 7.41 (IH, d, J= 8 i o Hz), 7.5-7.7 (4H, m), 8.29 (IH, s), 8.83 (IH, br s).

Synthesis Example 188

Production of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trifluorome1hyl)phenoxy]phenyl}amώo^

15 (i) Production of tert-butyl {2-[4-({3-methyl-4-[3-(trffluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate

A mixture of tert-butyl [2-(4-cWoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate (297 mg), 3-methyl-4-[3-(trifluoromethyl)phenoxy]aniline (401 mg) and isopropyl alcohol (2.97 mL) was stirred at 8O⁰C for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/l 0 — » 0/100) to give the title compound (528 mg) as a white powder.

¹H-NMR(CDCl₃) B 1.47 (9H, s), 2.21 (3H, s), 3.50 (2H, m), 4.46 (2H, m), 5.11 (IH, m), 6.58 (IH, d, J= 3 Hz), 6.97 (IH, d, J= 9 Hz), 7.0-7.2 (3H, m), 7.27 (IH, m), 7.39 (IH, t, J= 8 Hz), 7.69 (2H, m), 8.45 (IH, br s), 8.50 (IH, s). (ii) Production of 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirrddin-4-arnine tert-Butyl {2-[4-({3-me%l-4-[3-(trifluorome%l)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}carbamate (494 mg) was dissolved in dichloromethane (6.4 mL), trifluoroacetic acid (4.8 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (442 mg) as a powder. 1H-NMR (CDCl₃) δ 2.20 (3H, s), 3.30 (2H, t, J= 5 Hz), 4.46 (2H, t, J= 5 Hz), 6.61 (IH, d, J= 3 Hz), 6.95 (IH, d, J= 9 Hz), 7.0-7.5 (6H, m), 7.51 (IH, d, J= 3 Hz), 8.50 (IH, s). (ϋi) Production of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trffluorometnyl)phenoxy]phenyl}ammo)-5

The title compound (89 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-meth.yl-4-[3- (1iifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirddin-4-arnine (196 mg), 2- (methylsulfonyl)acetic acid (64 mg), l-e1hyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (133 mg), 1-hydroxybenzotriazole monohydrate (94 mg), triethylamine (0.319 mL) and N,N-dimethylformarnide (5.0 mL).

¹H-NMR (DMSOd₆) δ 2.14 (3H, s), 3.09 (3H, s), 3.45 (2H, m), 4.05 (2H, s), 4.56 (2H, t, J= 7 Hz), 6.47 (IH, d, J= 3 Hz), 7.04 (IH, d, J= 9 Hz), 7.17 (2H, m), 7.47 (IH, m), 7.59 (4H, m), 8.29 (IH, s), 8.55 (IH, br s), 8.67 (IH, t, J= 5.5 Hz). Synthesis Example 189

Production of 2-{2-[4-({3-metiiyl-4-[3-(1rifluorome1noxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethoxy}ethanol

The title compound (128 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methyl-4-[3-(trifluoromethoxy)phenoxy]aniUne (184 mg) and l-methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSOd₆) δ 2.12 (3H, s), 3.51 (4H, m), 3.84 (2H, t, J= 5 Hz), 4.63 (2H, t, J= 5 Hz), 4.73 (IH, t, J= 5 Hz), 6.49 (IH, d, J= 3 Hz), 6.87 (2H, m), 7.04 (2H, m), 7.47 (IH, t, J= 8 Hz), 7.59 (2H, m), 7.66 (IH, d, J= 3 Hz), 8.29 (IH, s), 8.82 (IH, br s). Synthesis Example 190

Production of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-

(τrifluorome1hoxy)ρhenoxy]phenyl}amirø

(i) Production of tert-butyl {2-[4-({3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}arnino)-5H- 5 pyrrolo[3,2-d]pyrirnidin-5-yl]ethyl}carbarnate tert-Butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate (297 mg) and 3- methyl4-[3-(trifluoromethoxy)phenoxy]aniline (425 mg) were dissolved in isopropyl alcohol (2.97 mL), and the mixture was stirred at 80°C for 16 hrs. After cooling to room temperature, the mixture was diluted with ethyl acetate (60 mL), and washed with aqueous sodium hydrogen carbonate (30 i o mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20

-> 0: 100) to give the title compound (563 mg) as a white powder.

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 2.20 (3H, s), 3.49 (2H, m), 4.46 (2H, m), 5.08 (IH, m), 6.59 (IH, d, J= 3 Hz), 6.78 (IH, m), 6.86 (2H, m), 6.97 (IH, m), 7.16 (IH, d, J= 3 Hz), 7.27 (2H, m), 7.69 (2H, is m), 8.43 (IH, br s), 8.50 (IH, s).

(ϋ) Production of 5-(2-anmoe1hyl)-N-{3-methyl-4-[3-(trrfluoromethoxy)phehoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine tert-Butyl {2-[4-({3-methyl-4-[3-(tήfluoromethoxy)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (523 mg) was dissolved in dichloromethane (6.4 mL), 0 trifluoroacetic acid (4.8 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), and washed with aqueous sodium hydrogen carbonate (40 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (420 mg) as a white powder. 1H-NMR (CDCl₃) δ 2.20 (3H, s), 3.30 (2H, t, J= 4.5 Hz), 4.46 (2H, t, J= 4.5 Hz), 6.62 (IH, d, J= 3 Hz), 6.85 (3H, m), 6.96 (IH, d, J= 9 Hz), 7.19 (IH, d, J= 3 Hz), 7.27 (IH, m), 7.44 (IH, dd, J= 2 Hz, 9 Hz), 7.50 (IH, d, J= 3 Hz), 8.50 (IH, s). (iii) Production of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trMuoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethy^ A solution of 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirrύdin-4-amine (174 mg), 2-(methylsulfonyl)acetic acid (54 mg), l-ethyl-3-(3- dime1hylarninopropyl)carbodiimide hydrochloride (112 mg), 1-hydroxybenzotriazole monohydrate (79 mg) and triethylamine (0.273 mL) in N,N-dimethylformamide (7.69 mL) was stirred at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate (80 mL), and washed with water (60 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > 92:8), and crystallized from dϋsopropyl ether to give the title compound (92 mg) as colorless crystals. 1H-NMR (DMSOd₆) δ 2.14 (3H, s), 3.10 (3H, s), 3.46 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.56 (2H, t, J= 6 Hz), 6.48 (IH, d, J= 3 Hz), 6.89 (2H, m), 7.06 (2H, m), 7.48 (IH, t, J= 8 Hz), 7.59 (3H, m), 8.30 (IH, s), 8.55 (IH, br s), 8.67 (IH, t, J= 6 Hz). melting point: 106-108⁰C

Synthesis Example 191

Production of N-[2-(4-{[3-cMoro-4-(3-cWorophenoxy)phenyl]amino}-5H-pyiτolo[3,2-d]pyrimidin- 5-yl)ethyl]-2-(methylsulfonyl)acetamide

(i) Production of tert-butyl 2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl)amino)-5H-pyrrolo[3,2- 5 d]pyrimidin-5-yl]ethylcarbamate

Amixture of tert-butyl 2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethylcarbamate (1.19 g), 3-chloro-4-(3-chlorophenoxy)aniline (1.22 g) and isopropyl alcohol (12.0 mL) was stirred at 80°C for 15 hrs. Under ice-cooling, aqueous sodium hydrogen carbonate was added, and the mixture was extracted with etfryl acetate. The organic layer was washed with brine, and dried over i o anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluenthexane/ethyl acetate=50/50 -> 100/0), and washed with diisopropyl ether-hexane to give the title compound (1.69 g) as crystals. 1H-NMR (CDCl₃) δ: 1.50 (9H, s), 3.4-3.6 (2H, m), 4.44.6 (2H, m), 5.0-5.1 (IH, m), 6.61 (IH, d, J= 2.6 Hz), 6.85-7.05 (2H, m), 7.07 (2H, d, J= 8.8 Hz), 7.18 (IH, d, J= 2.6 Hz), 7.2-7.3 (IH, m), 7.85- 15 7.95 (IH, m), 8.0-8.05 (IH, m), 8.52 (IH, s), 8.62 (IH, br s).

(ϋ) Production of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3 ,2- d]pyriπddm-4-arnine dihydrochloride

To a solution of tert-butyl 2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H- pyπ-olo[3,2-d]pyrirnidin-5-yl)ethylcarbamate (1.69 g) in tetrahydrofuran (32 mL) was added 2N 0 hydrochloric acid (16 mL). The reaction mixture was stirred at 65°C for 18 hrs and concentrated. Ethanol was added, and the mixture was concentrated again. Ethyl acetate and dϋsopropyl ether were added to the residue, and the precipitate was collected by filtration and washed with diisopropyl ether to give the title compound (1.50 g) as crystals.

¹H-NMR (DMSOd₆KX⁾Cl₃) δ: 3.3-3.6 (4H, m), 5.0-5.15 (2H, m), 6.71 (IH, d, J= 3.2 Hz), 6.9-7.0 5 (2H, m), 7.1-7.2 (IH, m), 7.22 (IH, d, J= 8.8 Hz), 7.3-7.45 (IH, m), 7.6-7.7 (IH, m), 7.87 (IH, d, J= 2.6 Hz), 8.05 (IH, d, J= 2.4 Hz), 8.2-8.4 (2H, m), 8.71 (IH, s).

(iii) Production of N-[2-(4-{[3-cUoro-4-(3-cMorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrirrύdin-5-yl)emyl]-2-(memylsιιlfonyl)acetarnide

To a solution of 5-(2-arninoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- i o pyrrolo[3,2-d]pyrirnidin-4~amine dihydrochloride (200 mg), 2-(methylsulfonyl)acetic acid (113 mg) and 1-hydroxybenzotriazole (122 mg) inN,N-dimethylformamide (5.0 mL) were added a solution of triethylamine (419 mg) mN,N-dimethylformarnide (1.25 mL) and l-ethyl-3-(3- dimethylammopropyl)carbodiimide hydrochloride (173 mg) under ice-cooling. After stirring the reaction mixture at room temperature for 16 hrs, water was added under ice-cooling, and the is mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluentethyl acetate/methanol=100/0 -> 80/20), and recrystallized from ethanol- ethyl acetate-diisopropyl ether to give the title compound (151 mg) as crystals. 1H-NMR (CDCl₃) δ: 3.13 (3H, s), 3.6-3.8 (2H, m), 3.99 (2H, s), 4.4-4.6 (2H, m), 6.62 (IH, d, J= 3.4 0 Hz), 6.85-6.95 (2H, m), 7.0-7.1 (2H, m), 7.2-7.3 (2H, m), 7.7-7.8 (IH, m), 7.95-8.0 (IH, m), 8.19 (IH, s), 8.52 (IH, s). melting point: 206-207°C

Synthesis Example 192

Production of 2-[{3-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyriniidm-5-yl]propyl}(methyl)

(i) Production of 4-cUoro-5-(3-chloropropyl)-5H-pyrrolo[3,2-d]pyrirnidine 5 To a solution of 4-cHoro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g) in N,N-dimethylformamide

(20 mL) was added cesium carbonate (4.89 g) under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. l-Bromo-3-chloropropane (1.89 g) was added and the mixture was stirred under ice-cooling for 1 hr and at room temperature for 32 hrs. The reaction mixture was poured into water (40 mL), and the mixture was extracted with ethyl acetate (60 mL><2). The organic layers i o were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20

— > 50:50) to give the title compound (1.87 g).

¹H-NMR (CDCl₃) δ: 2.35 (2H, m), 3.49 (2H, t, J= 6.0 Hz), 4.69 (2H, t, J= 6.6 Hz), 6.73 (IH, d, J=

3.0 Hz), 7.56 (IH, d, J= 3.0 Hz), 8.70 (IH, s). 15 (ii) Production of N-{3-chloro-4-[(3-3fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3,2- d]pyrirrddin-4-amine

A mixture of 4-cHoro-5-(3-cMoropropyl)-5H-pyrrolo[3,2-d]pyrirnidine (839 mg), 3-chloro-

4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and isopropyl alcohol (5 mL) was stirred at 8O⁰C for 1.5 hrs.

The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (30 mLx3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 -» 20:80) to give the title compound (1.19 g). ¹H-NMR (CDCl₃) δ: 2.36 (2H, m), 3.56 (2H, t, J- 5.7 Hz), 4.47 (2H, t, J= 6.9 Hz), 5.14 (2H, s), 6.60 (IH, d, J= 3.3 Hz), 6.73 (IH, br s), 6.94 (IH, d, J= 8.7 Hz), 7.02 (IH, m), 7.19-7.40 (5H, m), 7.65 (IH, d, J= 3.3 Hz), 8.49(1H, s).

(iii) Production of 2-[{3-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pvrimidin-5-yl]propyl}(me1hyl)animo]ethanol dώydrochloride A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H- pyiτolo[3,2-d]pyrimidm-4-amine (634 mg), 2-methylaminoethanol (534 mg) andN,N- dimethylformamide (5 mL) was stirred at room temperature for 64 hrs. After concentration under reduced pressure, saturated aqueous sodium hydrogen carbonate (10 mL) was added to the residue, and the mixture was extracted with ethyl acetate (55 mLx2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent, hexaneiethyl acetate=80:20 -» 0:100). 4N Hydrogen chloride-ethyl acetate solution (10 mL) was added to the obtained amorphous solid and, after concentration under reduced pressure, the residue was recrystallized from ethanol-ethyl acetate to give the title compound (523 mg). 1H-NMR (DMSO-d_δ) δ: 2.16-2.32 (2H, m), 2.74 (3H, s), 2.94-3.40 (4H, m), 3.62-3.80 (2H, m), 4.744.84 (2H, m), 5.31 (2H, s), 6.69 (IH, m), 7.20 (IH, m), 7.29-7.36 (5H, m), 7.43-7.50 (2H, m), 7.71 (IH, m), 8.03 (IH, br s), 8.64 (IH, s), 9.84 (IH, br s), 10.12 (IH, br s).

Synthesis Example 193

Production of N-{3-cMoro4-[(3-fluorobenzyl)oxy]phenyl}-5-[3-(dimethylamino)propyl]-5H- pyrrolo[3,2-d]pyrirnidin-4-anτine dihydrochloride

N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H-pyrrolo[3₅2- 5 d]pyrimidin-4-amine (560 mg) was dissolved in 2.0 M dimethylamine-tefrahydrofuran solution (5 mL), and the mixture was stirred at room temperature for 26 hrs. A 2.0 M dimethylamine- tetrahydrofuran solution (5 mL) was further added and the mixture was stirred at room temperature for 20 hrs. A 2.0 M dime&ylamine-tetrahydrofuran solution (10 mL) was further added, and the mixture was stirred at room temperature for 24 hrs. After concentration of the reaction mixture i o under reduced pressure, saturated aqueous sodium hydrogen carbonate (20 mL) was added to the residue, and the mixture was extracted with ethyl acetate (35 mLx2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 — > 20:80), and 4N hydrogen chloride-ethyl acetate solution (10 mL) was added to the obtained amorphous

15 solid. After concentration under reduced pressure, the residue was recrystallized from ethanol-ethyl acetate to give the title compound (428 mg).

¹H-NMR (DMSOd₆) δ: 2.18-2.26 (2H, m), 2.70 (6H, s), 2.94-3.04 (2H, m), 4.77-4.84 (2H, m), 5.30 (2H, s), 6.67 (IH, m), 7.19 (IH, m), 7.28-7.34 (4H, m), 7.43-7.51 (2H, m), 7.71 (IH, m), 8.04 (IH, m), 8.63 (IH, s), 9.87 (IH, br s), 10.74 (IH, br s). Synthesis Example 194

Production of 6-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a- tetraazabenzo[cd]azulene 5 A mixture of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-5-(3-chloropropyl)-5H- pyrrolo[3,2-d]pyrirnidin-4-arnine (839 mg), 3-chloro4-[(3-fluorobenzyl)oxy]aniline (1.10 g) and 1- mefhyl-2-pyrrolidone (5 mL) was stirred at 140°C for 1 hr. The reaction mixture was poured into water (10 mL) and adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate (40 mLx3), and the organic layers were combined and i o dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=60:40 — » 50:50) and further subjected to basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -» 0: 100). The object fraction was concentrated under reduced pressure. Chloroform-dϋsopropyl ether was added to the residue, and the solid was collected by filtration and dried. Recrystallization

15 from ethyl acetate gave the title compound (74.5 mg).

¹H-NMR (DMSO-d_δ) δ: 2.31 (2H, m), 3.88 (2H, m), 4.31 (2H, m), 5.27 (2H, s), 6.47 (IH, d, J= 3.0 Hz), 7.14-7.36 (5H, m), 7.42 (IH, d, J= 2.4 Hz), 7.47 (IH, m), 7.65 (IH, d, J= 3.0 Hz), 8.02 (IH, s). Synthesis Example 195

Production of 6-{3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a- tetraazabenzo[cd]azulene

(i) Production of 5-(3-cUoropropyl)-N-{3-cMoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}-5H- 5 pyrrolo[3,2-d]pyrirnidin-4-arnine

A mixture of 4-cUoro-5-(3-cMoropropyl)-5H-pyrrolo[3,2-d]pyrirnidine (789 mg), 3-chloro- 4-[3-(trifluoromethyl)phenoxy]aniline (1.09 g) and isopropyl alcohol (5 niL) was stirred at 80°C for 4.5 hrs. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate (30 mL) was added to the residue, and the mixture was extracted with ethyl acetate (40 i o mLx3). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 -> 20:80) to give the title compound (1.46 g). 1H-NMR (CDCl₃) δ: 2.39 (2H, m), 3.60 (2H, t, J= 5.6 Hz), 4.53 (2H, t, J= 6.9 Hz), 6.62 (IH, d, J= 3.3 Hz), 6.96 (IH, br s), 7.07 (IH, d, J= 8.7 Hz), 7.08-7.49 (6H, m), 7.87 (IH, m), 8.55 (IH, s). is (ii) Production of 6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-6,7,8,9-tetrahydro-3,5,6,9a- tetraazabenzo [cd]azulene

A mixture of 5-(3-chloropropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine (470 mg), potassium carbonate (270 mg) and ethylene glycol (10 mL) was stirred at room temperature for 18.5 hrs, and at 60⁰C for 4 hrs. The reaction mixture was 0 poured into aqueous sodium hydrogen carbonate (20 mL), and the mixture was extracted with ethyl acetate (50 ml>2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 -» 0:100), and the obtained solid was recrystallized from ethanol-water to give the title compound (116 mg).

5 ¹H-NMR (DMSOd₆) δ: 2.45 (2H, m), 3.99 (2H, t, J= 4.8 Hz), 4.34 (2H, t, J= 5.4 Hz), 6.65 (IH, d, J= 3.0 Hz), 7.06 (IH, d, J= 9.0 Hz), 7.16-7.22 (2H, m), 7.28 (IH, m), 7.33 (IH, d, J= 3.0 Hz), 7.37 (IH, m), 7.42 (IH, d, J= 2.4 Hz), 7.46 (IH, m), 8.36 (IH, s). Synthesis Example 196

j o Production of 2-{2-[7-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amiQo)-lH-pyrazolo[4,3- d]pyrimidin- 1 -yl} ethoxy } ethanol (i) Production of 2-{2-[7-(methyliMo)-lH-pyrazolo[4,3-d]pyrirrddin-l-yl]ethoxy}ethyl benzoate

A mixture of 7-(me%ltrύo)-lH-pyrazolo[4,3-d]pyrimidine (747 mg), 2-{2- [(methylsulfonyl)oxy]ethoxy} ethyl benzoate (1.43 g), potassium carbonate (931 mg) andN,N-

15 dimethylformamide (12 mL) was stirred at 6O⁰C for 4 hrs. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (50 mLx2). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 20:80), and further purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate^OilO — > 40:60) to give the title compound (533 mg). 1H-NMR (CDCl₃) δ: 2.67 (3H, s), 3.75 (2H, m), 4.01 (2H, m), 4.38 (2H, m), 4.87 (2H, t, J= 5.8 Hz), 7.38-7.48 (3H, m), 7.91-7.95 (2H, m), 8.11 (IH, s), 8.71 (IH, s).

5 (ϋ) Production of 2-{2-[7-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}arnino)-lH-pyrazolo[4,3- djpyrirnidin- 1 -yl] ethoxy } ethanol

A mixture of 2-{2-[7-(me1hylMo)-lH-pvrazolo[4,3-d]pyrirnidin-l-yl]e1hoxy}ethyl benzoate (200 mg), 3-cMoro4-[(3-fluorobenzyl)oxy]aniline (140 mg), pyridine hydrochloride (96 mg) and l-methyl-2-pyrrolidone (5 mL) was stirred at 140⁰C for 16.5 hrs. The reaction mixture l o was poured into saturated aqueous sodium hydrogen carbonate (30 mL), and extracted with ethyl acetate (30 mLx3). The organic layers were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 -> 20:80). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol

15 (5 mL). IN Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at room temperature for 11.5 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (45 mL><2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl 0 acetate=80:20 -> 0: 100) and recrystallized from ethanol-ethyl acetate to give the title compound (78 ing)-

¹H-NMR (DMSO-de) δ: 3.30-3.55 (4H, m), 3.87 (2H, m), 4.67 (IH, m), 4.86 (2H, m), 5.26 (2H, s),

7.14-7.35 (4H, m), 7.46 (IH, m), 7.60 (IH, d, J= 8.4 Hz), 7.92 (IH, m), 8.18 (IH, s), 8.35 (IH, s), 8.99 (lH, br s).

Production of 2-{2-[7-({3-cMoro4-[3-(trMuoromethyl)phenoxy]phenyl}amino)-lH-pyrazolo[4,3- 5 d]pyrirnidin-l-yl]ethoxy}ethanol

A mixture of 2-{2-[7-(me1hyltMo)-lH-pyrazolo[4,3-d]pyrhrήdin-l-yl]e1hoxy}e1hyl benzoate (328 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (264 mg), pyridine hydrochloride (159 mg) and l-methyl-2-pyrrolidone (7.5 mL) was stirred at 140°C for 33.5 hrs. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (15 mL), and o extracted with ethyl acetate (35 mLx2). The organic layers were combined and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 — > 0:100). The object fraction was concentrated under reduced pressure and the residue was dissolved in methanol (5 mL). IN Aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at 5 room temperature for 2 hrs. After concentration of the reaction mixture under reduced pressure, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mLx2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 0: 100) and recrystallized from ethyl acetate-hexane to give the title compound (50 mg)-

¹H-NMR (DMSOd₆) δ: 3.40-3.55 (4H, m), 3.88 (2H, m), 4.68 (IH, m), 4.89 (2H, m), 7.20-7.24 (2H, m), 7.33 (IH, d, J= 8.7 Hz), 7.47 (IH, d, J= 7.5 Hz), 7.62 (IH, m), 7.77 (IH, m), 8.13 (IH, s), 8.22 (IH, s), 8.44 (IH, m), 9.23 (IH, br s). 5 Synthesis Example 198

Production of 2-{2-[4-({3-cWoro-4-[(3-fluorobenzyl)oxy]phenyl}amMo)-6-methyl-5H-pyrrolo[3,2- d]pyrimidin-5-yl]efhoxy}ethanol

(i) Production of 4-phenoxy-6-prop-l-yn-l-ylpyrirnidin-5-arnine i o 4-Iodo-6-phenoxypyrimidin-5-arnine (5.00 g) was dissolved in a mixed solvent of N₃N- dimethylformamide (100 mL)/triethylamine (50 mL), and l-(trimethylsilyl)-l-propyne (3.3 mL), trans-dicUorobis(triphenylphosphine)palladium(π) (557.7 mg), triphenylphosphine (421.1 mg), copperQ iodide (303.0 mg) and potassium fluoride (1.29 g) were sequentially added. The mixture was stirred at 60°C under an argon stream for 16 hrs. The reaction mixture was treated with

15 saturated aqueous sodium hydrogen carbonate solution and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 50:50) to give the title compound (2.64 g) as a orange solid. ¹H-NMR (CDCl₃) δ:2.19 (3H,s),4.36 (2H,br s),7.07-7.22 (2H,m),7.22-7.34 (lH,m),7.35-7.54

(2H,m),8.08 (lH,s).

(ϋ) Production of 6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine

4-Phenoxy-6-prop-l-yn-l-ylpyrknidin-5-arnine (776.0 mg) was dissolved in 5 tetrahydrofuran (30 mL) and cooled to 0°C. To this solution was added dropwise a 1.0 M solution (4 mL) of potassium tert-butoxide in tetrahydrofuran, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and i o purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33 — » 20:80) to give the title compound (578.6 mg) as a white solid.

¹H-NMR (CDCl₃) δ:2.54 (3H,s),6.44 (lH,q,J= 1.0 Hz),7.21-7.30 (3H,m), 7.41-7.48 (2H,m),8.47 (lH,s),8.55 (lH,br s). (in) Production of 2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethoxy]ethyl

15 benzoate

6-Methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrirnidine (299.9 mg) and 2-{2- [(methylsulfonyl)oxy]ethoxy}ethyl benzoate (464.1 mg) were dissolved in N₅N- dimethylformamide (7 mL), potassium carbonate (431 mg) was added, and the mixture was stirred at 6O⁰C for 21 hr. Water was added to the reaction mixture, and the mixture was extracted with 0 ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 20:80) to give the title compound (517.8 mg) as a yellow oil. ¹H-NMR (CDCl₃) δ: 2.50 (3H₃ s), 3.62-3.74 (2H, m), 3.92 (2H, t, J= 5 Hz), 4.33-4.44 (2H, m), 4.57 (2H, t, J= 5 Hz), 6.36 (IH, s), 7.15-7.34 (3H, m), 7.34-7.51 (4H, m), 7.51-7.65 (IH, m), 7.87-8.00 (2H, m), 8.40 (lH, s).

(iv) Production of 2-{2-[4-({3-cUoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H- 5 pyrrolo[3,2-d]pyrimidin-5-yl]e1hoxy}ethyl benzoate

A mixture of 2-[2-(6-me1^1-4-phenoxy-5H-pyrrolo[3^-d]pyrimidin-5-yl)ethoxy]efhyl benzoate (92.3 mg), 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (86.3 mg), pyridine hydrochloride (81.6 mg) and phenol (156.1 mg) was stirred at 120°C for 3 hrs, and at 140°C for 5.5 hrs. Further, pyridine hydrochloride (77.6 mg) and phenol (188.7 mg) were added, and the mixture was stirred at i o 140°C for 22.5 hrs. The reaction mixture was diluted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=50:50 -» 0: 100) to give the title compound (33.3 mg) as a purple oil. 1H-NMR (CDCl₃) δ: 2.43 (3H, s), 3.88-3.97 (2H, m), 4.00 (2H, t, J= 4.4 Hz), 4.42-4.55 (4H, m), s 5.04 (2H, s), 6.38 (IH, s), 6.71 (IH, d, J= 8.8 Hz), 6.93-7.09 (IH, m), 7.13-7.42 (6H, m), 7.46-7.58 (IH, m), 7.65 (IH, d, J= 2.6 Hz), 7.74-7.85 (2H, m), 8.40 (IH, s), 8.48 (IH, s). (v) Production of 2-{2-[4-({3-cMoro-4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H- pyrrolo[3,2-d]pyrirnidrn-5-yl]ethoxy}ethanol

2-{2-[4-({3-CWoro4-[(3-fluorobenzyl)oxy]phenyl}amino)-6-methyl-5H-pyrrolo[3,2-0 d]pyrimidrn-5-yl]ethoxy}ethyl benzoate (90.0 mg) was dissolved in methanol (1 mL), IN aqueous sodium hydroxide solution (0.3 mL) was added, and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was neutralized with IN hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=33:67 — > 0:100) to give the title compound (43.9 mg) as a pale-yellow powder.

¹H-NMR (DMSOd₆) δ 2.45 (3H, s), 3.46-3.52 (4H, m), 3.82 (2H, t, J= 4.7 Hz), 4.52 (2H, t, J= 4.3 5 Hz), 4.64-4.80 (IH, m), 5.23 (2H, s), 6.30 (IH, s), 7.10-7.24 (2H, m), 7.26-7.38 (2H, m), 7.41-7.55 (2H, m), 7.82 (IH, d, J= 2.8 Hz), 8.21 (IH, s), 8.68 (IH, s). Synthesis Example 199

Production of 2-{2-[4-({3-cMoro-4-[3-(trMuoromemoxy)phenoxy]phenyl}amino)-6-methyl-5H- i o pyiτolo[3,2-d]pyrirnidin-5-yl]ethoxy}ethanol

The title compound (288.2 mg ) was obtained as a pale pink oil by the reaction in the same manner as in Synthesis Example 198 (iv) using 2-[2-(6-methyl-4-phenoxy-5H-pyrrolo[3,2- 25 d]pyrimidin-5-yl)ethoxy]ethyl benzoate (271.0 mg), 3-chloro-4-[3-

(1rifluoromemoxy)phenoxy]aniline (297.3 mg), pyridine hydrochloride (235.0 mg) and phenol

(497.9 mg).

¹H-NMR (CDCl₃) δ: 2.45 (3H, s), 3.92-4.00 (2H, m), 4.04 (2H, t, J= 4.4 Hz), 4.45-4.55 (4H, m),

6.42 (IH, s), 6.75-6.85 (3H, m), 6.85-6.96 (2H, m), 7.19-7.37 (3H, m), 7.45-7.53 (IH, m), 7.75-7.82 0 (2H, m), 7.85 (IH, d, J= 2.8 Hz), 8.46 (IH, s), 8.73 (IH, br s). (ϋ) Production of 2-{2-[4-({3-cUoro-4-[3-(trifluoromelhoxy)phenoxy]phenyl}amiπo)-6-niethyl- 5H-pyrrolo[3,2-d]pyrirnidin-5-yl]ethoxy}ethanol

The title compound (119.1 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 198 (v) using 2-{2-[4-({3~chloro-4-[3- 5 (tiifluorome1hoxy)phenoxy]phenyl}am benzoate (281.5 mg), IN aqueous sodium hydroxide solution (0.6 mL) and methanol (2 mL). 1H-NMR (DMSOd₆) δ 2.47 (3H, s), 3.44-3.56 (4H, m), 3.81-3.89 (2H, m), 4.56 (2H, t, J= 4.5 Hz), 4.714.79 (IH, m), 6.35 (IH, s), 6.88-6.95 (2H, m), 7.06-7.14 (IH, m), 7.26 (IH, d, J= 9 Hz), 7.50 (IH, t, J= 9 Hz), 7.66 (IH, dd, J= 9 Hz, 2.5 Hz), 8.01 (IH, d, J= 2.5 Hz), 8.30 (IH, s), 8.99 (IH, br s). i o Synthesis Example 200

Production of 4-({3-cMoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5-[2-(2- hydroxyemoxy)emyl]-5H-pyiτolo[3,2-d]pyrimidme-6-carbonitrile

(i) Production of 4-(3,3-diethoxyprop-l-yn-l-yl)-6-phenoxypyrimidin-5-amine 5 The title compound (6.20 g) was obtained as a brown oil by the reaction in the same manner as in Synthesis Example 9 (iv) using 4-iodo-6-phenoxypyrirnidin-5-amine (7.0 g), 3,3- diethoxyprop-1-yne (3.8 mL), trar«-dicMorobis(triphenylphosphine)palladium(ir) (783.3 mg), copper(T) iodide (255.2 mg) and acetonitrile (160 mL)/1rie1hylamine (120 mL). 1H-NMR (CDCl₃) δ: 1.29 (6H, t, J= 7.2 Hz), 3.62-3.77 (2H, m), 3.77-3.91 (2H, m), 4.48 (2H, br s),0 5.56 (IH, s), 7.14-7.21 (2H, m), 7.27-7.33 (IH, m), 7.39-7.50 (2H, m), 8.11 (IH, s). (ϋ) Production of 6-(diethoxyme1hyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyriinidine

4-(3,3-Diethoxyprop-l-yn-l-yl)-6-phenoxypyrimidin-5-amine (2.30 g) was dissolved in 1- methyl-2-pyrrolidone (7.5 mL), and the mixture was cooled to 0°C. A solution (7.6 mL) of potassium tert-butoxide in 1.0 M tetrahydrofuran was added dropwise to this solution, and the mixture was stirred at 0°C for 30 min. and at room temperature for 1.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexanerethyl acetate=90:10 — > 50:50) to give the title compound (1.34 g) as a pale orange solid. ¹H-NMR (CDCl₃) δ: 1.29 (6H, t, J= 7.1 Hz), 3.52-3.75 (4H, m), 5.78 (IH, s), 6.66 (IH, br d, J= 2.2 Hz), 7.26-7.34 (3H, m), 7.42-7.52 (2H, m), 8.52 (IH, s), 8.95 (IH, br s). (iii) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbaldehyde

6-(Die1hoxyme1hyl)-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (3.15 g) was dissolved in tetrahydrofuran (40 mL), IN hydrochloric acid (40 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was neutralized with IN aqueous sodium hydroxide solution, and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=l/l . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was collected by filtration and dried to give the title compound (2.17 g) as a yellow powder. 1H-NMR (DMSO-dδ) δ: 7.25-7.40 (3H, m), 7.43-7.58 (3H, m), 8.44 (IH, s), 10.06 (IH, s), 13.26 (IH, s). (iv) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrirnidiαe-6-carboxylic acid

4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbaldehyde (2.17 g) was dissolved in dimethyl sulfoxide (21 mL) and a solution of sodium dihydrogen phosphate (5.45 g) in water (14 mL) was added. A solution of sodium chlorite (2.06 g) in water (14 mL) was added dropwise to this solution, and the mixture was stirred for 2 hrs. Saturated aqueous sodium hydrogen carbonate solution was gradually added to the reaction mixture, and the pH of the solution was adjusted to 2-3 5 with IN hydrochloric acid. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether and dried to give the title compound (2.40 g) as a white powder. 1H-NMR (DMSOd₆) δ: 7.09 (IH, s), 7.23-7.36 (3H, m), 7.41-7.54 (2H, m), 8.36 (IH, s), 12.82 (IH, s). (v) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide i o Thionyl chloride (7 mL) was added to 4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6- carboxylic acid (465.0 mg) and the mixture was stirred at 75⁰C for 2 hrs. The reaction mixture was concentrated under reduced pressure and suspended in tetrahydrofuran (10 mL). The above- mentioned suspension was gradually added to aqueous ammonia (20 mL) and the precipitate was collected by filtration. The filtrate was extracted with a mixed solvent of ethyl is acetate/tetrahydrofuran=l/l, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitate was collected by filtration, combined with the precipitate collected earlier by filtration and dried to give the title compound (427.4 mg) as a pale-yellow powder. 1H-NMR (DMSO-de) δ: 7.25 (IH, s), 7.27-7.35 (3H, m), 7.39-7.57 (2H, m), 7.75 (IH, s), 8.17 (IH, 0 s), 8.36 (IH, s), 12.58 (IH, s).

(vi) Production of 4-phenoxy-5H-pyrrolo[3,2-d]pyrirnidine-6-carbonitrile

4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carboxamide (1.67 g) was suspended in phosphorus oxychloride (20 mL), and the suspension was stirred at 70°C for 3 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (25 mL). Water and aqueous ammonia were added to the solution, and the mixture was extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=l/l . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated 5 under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90: 10 -» 67:33) to give the title compound (1.07 g) as a pale-yellow powder.

¹H-NMR (CDC13) δ: 7.29-7.39 (3H, m), 7.46-7.55 (2H, m), 7.59 (IH₅ s), 8.47 (IH, s), 13.76 (IH, s). (vii) Production of 2-{2-[4-({3-cMoro-4-[3-(1rrfluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H- i o pyrrolo[3,2-d]pyrirnidin-5-yl]ethoxy}ethyl benzoate

4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile (240.4 mg) was dissolved inN,N- dimethyrformamide (5 mL), and 2-{2-[(me1hylsulfonyl)oxy]ethoxy}ethyl benzoate (354.1 mg) and potassium carbonate (354.8 mg) were added. The title compound (266.5 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 198 (iii) using the mixture is prepared above.

¹H-NMR (CDC13) δ: 3.73-3.79 (2H, m), 3.96 (2H, t, J= 4.9 Hz), 4.37-4.43 (2H, m), 4.83 (2H, t, J= 4.9 Hz), 7.17 (IH, s), 7.18-7.23 (2H, m), 7.27-7.35(1H, m), 7.36-7.49 (4H, m), 7.51-7.58 (IH, m), 7.85-7.92 (2H, m), 8.49 (IH, s).

(viϋ) Production of 2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-6-cyano-5H- 0 pyrrolo[3,2-d]pyrirnidin-5-yl]ethoxy}ethyl benzoate

The title compound (282.6 mg) was obtained as a yellow oil by the reaction in the same manner as in Synthesis Example 198 (iv) using 2-{2-[4-({3-chloro-4-[3-

(trffluoromemyl)phenoxy]phenyl}ammo)-6^ benzoate (261.5 mg), 3-cWoro-4-[3-(1riJluorometh.yl)phenoxy]aniline (264.4 mg), pyridine hydrochloride (221.6 mg) and phenol (461.6 mg).

¹H-NMR (CDCl₃) δ: 3.96-4.06 (2H, m), 4.16-4.22 (2H, m), 4.45-4.54 (2H₅ m), 4.68-4.79 (2H, m), 6.80 (IH, d, J= 8.8 Hz), 7.01-7.09 (IH, m), 7.14-7.20 (IH, m), 7.24 (IH, s), 7.27-7.53 (6H, m), 5 7.68-7.76 (2H, m), 7.92 (IH, d, J= 2.5 Hz), 8.53 (IH, s), 8.95 (IH, s).

(k) Production of 4-({3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5-[2-(2- hydroxye1hoxy)e1hyl]-5H-pyrrolo[3,2-d]pyrimidine-6-carbonitrile

The title compound (143.2 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 198 (v) using 2-{2-[4-({3-chloro-4-[3- i o (trifluoromethyl)phenoxy]phenyl} amino)-6-cyano-5H-pyrrolo [3 ,2-d]pyrimidin-5-yl]ethoxy } ethyl benzoate (282.6 mg), IN aqueous sodium hydroxide solution (0.6 mL) and methanol (3 mL). 1H-NMR (CDCl₃) δ: 1.77 (IH, t, J= 4.4 Hz), 3.74-3.88 (4H, m), 4.084.16 (2H, m), 4.70-4.80 (2H, m), 7.05-7.15 (2H, m), 7.16-7.21 (IH, m), 7.25 (IH, s), 7.30-7.36 (IH, m), 7.43 (IH, t, J= 7.8 Hz), 7.67 (IH, dd, J= 8.8 Hz, 2.8 Hz), 7.96 (IH, d, J= 2.8 Hz), 8.58 (IH, s), 9.03 (IH, s).

Production of 2-{3-[4-({3-cUoro4-[3-(trffluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]propoxy } ethanol hydrochloride

(i) Production of 3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl methanesulfonate 0 60% Sodium hydride (8.05 g) was suspended in N,N-dimethylformamide (80 mL), and the suspension was cooled to 0⁰C. A solution of propane-l,3-diol (7.2 mL) inN,N-dimefhylformamide (10 mL) was added dropwise, and the mixture was stirred at 0°C for 1 hr. A solution of 2-(2- bromoethoxy)tetrahydro-2H-pyran (4.0 mL) inN,N-dimethylformamide (10 mL) was added dropwise to the reaction solution, and the mixture was stirred at O⁰C for 2 hrs. Saturated aqueous 5 ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), andtriethylamine (9 mL) and methanesulfonyl chloride (2.3 mL) were added. The mixture was stirred at room temperature for 3 hrs. Water was added to the reaction i o mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 20:80) to give the title compound (3.78 g) as a colorless oil. 1H-NMR (CDCl₃) δ: 1.45-1.66 (4H,m),1.66-1.92 (2H^n), 1.96-2.09 (2H,m),3.02 (3H,s),3.45-3.68 is (6H,m),3.81-3.94 (2H,m), 4.36 (2H, t, J= 6.2 Hz), 4.62 (IH, dd, J= 4.4 Hz, 2.7 Hz).

(ϋ) Production of 4-chloro-5-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl}-5H-pyrrolo[3,2- d]pyrimidine

4-CUoro-5H-pyrrolo[3,2-d]pyrirnidine (203.6 mg), 3-[2-(tetrahydro-2H-pyran-2- yloxy)ethoxy]propyl methanesulfonate (559.3 mg) was dissolved iαN,N-dimethyrformamide (4 0 mL), cesium carbonate (1.30 g) was added, and the mixture was stirred at 40°C for 4.5 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexaneiethyl acetate=67:33 -> 20:80) to give the title compound (380.2 mg) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.44-1.70 (4H, m), 1.70-1.95 (2H, m), 1.95-2.24 (2H, m), 3.23-3.43 (2H, m),

3.45-3.69 (2H, m), 3.78-4.02 (2H, m), 4.53-4.75 (3H, m), 6.69 (IH, d, J= 3.3 Hz), 7.66 (IH, d, J= 5 3.3 Hz), 8.69 (IH, s).

(iϋ) Production of 2-{3-[4-({3-cUoro4-[3-(triiluoromethyl)phenoxy]phenyl}amino)-5H- pyiτolo[3,2-d]pvrimidin-5-yl]propoxy}etnanol hydrochloride

4-Chloro-5-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]propyl}-5H-pyrrolo[3,2- djpyrimidine (380.2 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3- i o (trifluoromethyl)phenoxy]aniline (419.2 mg) was added, and the mixture was stirred at 80°C for 18 hrs. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=50:50 -> 15 0:100), and the mixture was dissolved in ethyl acetate (4 mL). 4N Hydrochloric acid-ethyl acetate

(0.3 mL) was added to this solution, and the precipitate was collected by filtration, and dried to give the title compound (398.2 mg) as a white solid.

¹H-NMR (CDCl₃) δ: 1.86-2.02 (2H, m), 3.22 (2H, t, J= 5.8 Hz), 3.27-3.40 (2H, m), 3.41-3.55 (2H, m), 4.53-4.69 (2H, m), 6.50 (IH, d, J= 3.0 Hz), 7.16-7.26 (2H, m), 7.30 (IH, d, J= 8.9 Hz), 7.47 (IH, 0 d, J= 7.7 Hz), 7.56-7.76 (2H, m), 7.97 (IH, s), 8.35 (IH, s), 8.61 (IH, s).

Synthesis Example 202

Production of 2-[4-({3-cMoro-4-{3-(trifluoromethyl)phenoxy}phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide

(i) Production of ethyl [4-({3-cWoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- 5 pyrrolo[3,2-d]pyrimidin-5-yl]acetate

The title compound (221.2 mg) was obtained as an orange oil by the reaction in the same manner as in Synthesis Example 201 (iϋ) using ethyl (4-cWoro-5H-pyiτolo[3,2-d]pyrimidin-5- yl)acetate (119.3 mg), 3-cMoro-4-[3-(1rifiuorome1hyl)phenoxy]anUine (171.3 mg) andisopropyl alcohol (3 mL). o ¹H-NMR (CDCl₃) δ: 1.37 (3H, t, J= 7 Hz), 4.37 (2H₅ q, J= 7 Hz), 4.98 (2H, s), 6.66 (IH, d, J= 3.3

Hz), 7.09 (IH, d, J= 8.8 Hz), 7.09-7.14 (IH, m), 7.17-7.22 (IH, m), 7.24 (IH, d, J= 3.3 Hz)₅7.32 (IH, d, J= 7.8 Hz)₅ 7.42 (IH, t, J= 7.8 Hz), 7.53 (IH₅ dd₅ J= 8.8 Hz, 2.8 Hz)₅7.83 (IH, d, J= 2.8 Hz)₅ 8.52-8.63 (2H₅ m).

(ii) Production of [4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3₅2-5 d]pyrimidin-5-yl]acetic acid

Ethyl [4-({3-cMoro4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3₅2- d]pyrimidin-5-yl]acetate (221.2 mg) was dissolved in a mixed solvent of tetrahydrofuran (1.5 mL)/ethanol (1.5 mL), IN aqueous sodium hydroxide solution (0.6 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was adjusted to pH 2-3 with IN o hydrochloric acid and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran=l/l . The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was collected by filtration and dried to give the title compound (169.8 mg) as a yellow powder.

¹H-NMR (DMSOd₆) δ: 5.62 (2H, s), 6.70 (IH, d, J= 3.0 Hz), 7.22-7.31 (2H, m), 7.35 (IH, d, J= 5 8.8 Hz), 7.51 (IH, d, J= 8 Hz), 7.59 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.65 (IH, t, J= 8 Hz)₅7.86 (IH, d,

J= 2.5 Hz), 7.95 (IH, d, J= 3.0 Hz), 8.70 (IH, s), 9.99 (IH, s).

(in) Production of 2-[4-({3-cUoro-4-{3-(trrfluoromethyl)phenoxy}phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidm-5-yl]-N-[2-(methylsulfonyl)ethyl]acetamide

[4-({3-CUoro-4-[3-(trifluoromethyl^ i o 5-yl]acetic acid (149.3 mg) was dissolved mN,N-dmethylformamide (1.6 mL), 2-

(methylsulfonyl)ethanamine (60.3 mg), lH-l,2,3-benzotriazol-l-ol (67.8 mg), triethylamine (0.15 mL) andN-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride (93.0 mg) were added, and the mixture was stirred at room temperature for 17 hrs. Moreover, 2-

(methylsurfonyl)ethanamine (120.6 mg), lH-l,2,3-benzotriazol-l-ol (134.6 mg), triethylamine (0.3 is mL) and N-[3-(dimethylarnmo)propyl]-N'-e1hylcarbodiimide hydrochloride (181.4 mg) were added, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue was separated and purified by silica gel column chromatography (eluent, ethyl 0 acetate:methanol=l 00:0 — > 90:10), and basic silica gel column chromatography (eluent, hexane:ethyl acetate=33:67 -» 0:100 — > ethyl acetate:methanol=90:10) to give the title compound

(20.3 mg) as a white powder.

¹H-NMR (DMSO-de) δ: 2.98 (3H, s), 3.27 (2H, t, J= 6.9 Hz), 3.50-3.61 (2H, m), 5.12 (2H, s), 6.54 (IH, d, J= 3.0 Hz), 7.15-7.26 (2H, m), 7.33 (IH, d, J- 8.8 Hz), 7.47 (IH, d, J- 8.0 Hz), 7.56-7.68 (3H, m), 8.04 (IH, d, J= 2.5 Hz), 8.38 (IH, s), 9.07 (IH, t, J= 5.8 Hz), 9.97 (1H_S s).

Synthesis Example 203

5 Production of 4-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]but-2-yn- 1 -ol

(i) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-ol

60% Sodium hydride (1.39 g) was suspended in telrahydrofuran (50 mL), and the suspension was cooled to 0⁰C, a solution of but-2-yne-l,4-diol (3.0 g) intetrahydrofuran (20 mL) i o was added dropwise, and the mixture was stirred at room temperature for 1 hr. tert-

Butyldimethylsilyl chloride (5.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated 15 and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=l 00:0 -> 80:20) to give the title compound (1.48 g) as a colorless oil.

¹H-NMR(CDCl₃) δ: 0.12 (6H,s),0.91 (9H,s),1.60-1.66 (lH,m),4.27-4.33 (2H,m),4.36 (2H,t, J= 1.8

Hz).

(ii) Production of 4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-yl methanesurfonate 0 4-{[Tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-ol (701.4 mg) was dissolved in ethyl acetate (15 mL), and the solution was cooled to 0°C. Triethylamine (1.1 mL) and methanesulfonyl chloride

(0.3 mL) were added, and the mixture was stirred at 0⁰C for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=90:10 -» 50:50) to give the title compound (469.7 mg) as a colorless oil.

¹H-NMR(CDCl₃) 6:0.12 (6H,s),0.91 (9H,s),3.12 (3H,s), 4.37 (2H,t, J= 1.9 Hz),4.89 (2H,t, J= 1.9

Hz).

(iii) Production of 5-(4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-yl)-4-chloro-5H-pyrrolo[3,2- djpyrimidine

The title compound (431.1 mg) was obtained as a yellow oil by the reaction in the same manner as in Synthesis Example 201 (ϋ) using 4-cHoro-5H-pyrrolo[3,2-d]pyrimidine (211.9 mg),

4-{[tert-butyl(dimethyl)silyl]oxy}but-2-yn-l-yl methanesulfonate (464.0 mg), cesium carbonate

(672.7 mg) andN,N-dimethylformamide (5 mL). 1H-NMR (CDCl₃) δ: 0.07 (6H, s), 0.87 (9H, s), 4.35 (2H, t, J- 2 Hz)₅ 5.33 (2H, t, J= 2 Hz), 6.76 (IH, d, J= 3.3 Hz), 7.69 (IH, d, J= 3.3 Hz), 8.72 (IH, s).

(iv) Production of 4-[4-({3-cUoro-4-[3-(Mfluoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]but-2-yn- 1 -ol

5-(4-{[Tert-butyl(dmeihyl)silyl]o (408.3 mg) was dissolved in isopropyl alcohol (7 mL), 3-chloro-4-[3-

(trifluoromethyl)phenoxy] aniline (421.0 mg) was added, and the mixture was stirred at 80°C for 6 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in tetrahydrofiiran (6 mL), a 1.0 M solution (2 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The 5 organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=67:33 — » 20:80) and crystallized from hexane/ethyl acetate to give the title compound (425 mg) as white crystals.

¹H-NMR (CDCl₃) δ: 4.07-4.13 (IH, m), 4.45-4.52 (2H, m), 5.01-5.06 (2H, m), 6.44 (IH, d, J= 3.3 i o Hz), 7.06-7.16 (3H, m), 7.18-7.22 (IH, m), 7.33 (IH, d, J= 8 Hz), 7.43 (IH₅1, J= 8 Hz)₅ 7.57 (IH, dd, J= 8.8 Hz₅2.5 Hz)₅7.82 (IH₅ s), 7.95 (IH₅ d, J= 2.5 Hz)₅ 8.40 (IH₅ s). Synthesis Example 204

Production of (2E)-4-[4-({3-cWoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- 5 d]pyrirnidin-5-yl]but-2-en-l-ol

70% Sodium bis(2-methoxyethoxy)aluminum hydride in toluene solution (0.8 mL) was dissolved in tetrahydrofuran (4 mL), and the solution was cooled to O⁰C. A solution of 4-[4-({3- cUoro-4-[3-(Mfluoromethyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2-d]pyrimidm-5-yl]but-2-yn-l- ol (262.4 mg) in tetrahydrofuran (10 mL) was added dropwise, and the mixture was stirred at 0°C0 for 2 hrs. To the reaction mixture was added 10% aqueous potassium carbonate solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=33 :67 -> 0:100) and crystallized from hexane/ethyl acetate to give the title compound (195.9 mg) as white crystals.

¹H-NMR (DMSO-de) δ: 3.81-3.92 (2H, m), 4.75 (IH, t, J= 5.5 Hz), 5.17 (2H, m), 5.56 (IH, br d, J= 15 Hz), 5.80 (IH, br d, J= 15 Hz), 6.53 (IH, d, J= 3.0 Hz), 7.16-7.26 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.57-7.74 (3H, m), 7.98 (IH, d, J= 2.2 Hz), 8.36 (IH, s), 8.48 (IH, s). Synthesis Example 205

Production of 3-[4-({3-cMoro-4-[3-(τMuoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pvrimidin-5-yl]propane-l,2-diol

(i) Production of 3-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)propane-l,2-diyl dibenzoate

A mixture of 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (500 mg), 3-bromopropane-l,2-diyl dibenzoate (1.77 g), cesium carbonate (1.59 g) and N,N-dime&ylformamide (6.5 mL) was stirred at 80°C for 4 hrs. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (80 mL). The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 -» 40/60) to give the title compound (401 mg) as a white powder. ¹H-NMR (CDC13) δ 4.58 (IH, dd, J= 5 Hz, 12 Hz), 4.73 (IH, dd, J= 5 Hz, 12 Hz), 4.84 (IH, dd, J= 9 Hz, 15 Hz), 5.11 (IH, dd, J= 15 Hz, 5 Hz), 5.84 (IH, m), 6.69 (IH, d, J= 3 Hz), 7.3-7.7 (7H, m), 7.91 (2H, m), 8.02 (2H, m), 8.69 (IH, s).

(ii) Production of 3-[4-({3-cUoro-4-[3-(1rffluoromethyl)phenoxy]phenyl}amino)-5H--pyrrolo[3₅2- d]pyrimidin-5-yl]propane- 1 ,2-diol

5 The title compound (180 mg) was obtained as colorless crystals by the method in the same manner as in Synthesis Example 183 using 3-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propane- 1,2-diyl dibenzoate (250 mg), 3-chloro4-[3-(trifluoromethyl)phenoxy]anihiie (280 mg) and 1- methyl-2-pyrrolidone (1.14 mL).

¹H-NMR (DMSOd₆) δ 3.47 (2H, m), 3.94 (IH, m), 4.50 (2H, m), 5.18 (IH, br s), 6.52 (2H, d, J= 3 l o Hz), 7.20 (2H, m), 7.33 (IH, d, J= 9 Hz), 7.45 (IH, d, J= 8 Hz), 7.64 (3H, m), 8.04 (IH, d, J= 3 Hz), 8.35 (IH, s), 10.03 (IH, br s).

Synthesis Example 206

Production of 2-(2-{4-[{3-cUoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}(methyl)amino]-5H- 5 pyrrolo[3,2-d]pyrirnidin-5-yl}ethoxy)ethanol

The title compound (127 mg) was obtained by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (150 mg), 3-cUoro-N-memyl-4-[3-(trifluoromethyl)phenoxy]aniline (196 mg) and 1- methyl-2-pyrrolidone (0.863 mL). 0 ¹H-NMR (CDCl₃) δ 3.38 (2H, t, J= 4.5 Hz), 3.48 (2H, t, J= 4.5 Hz), 3.58 (3H, s), 3.62 (2H, m), 4.00 (2H, t, J= 5 Hz), 5.08 (IH, br s), 6.64 (IH, dd, J= 3 Hz, 9 Hz), 6.70 (IH, d, J= 3 Hz), 6.72 (IH, s), 6.97 (2H, m), 7.09 (2H, m), 7.40 (2H, m), 8.79 (IH, s).

Synthesis Example 207

5 Production of N-(2-{4-[{3-cMoro^-[3-(trifluoromethyl)phenoxy]phenyl}(methyl)aπiino]-5H- pyrrolo[3,2-d]pyrimidin-5-yl} ethyl)-2-(methylsulfonyl)acetamide hydrochloride

A mixture of tert-butyl [2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate (297 mg), 3-cUoro-N-methyl-4-[3-(trifluorornethyl)phenoxy]aniline (453 mg) and l-methyl-2- pyrrolidone (1.99 mL) was stirred at 120⁰C for 16 hrs. To the reaction mixture was added 2N i o hydrochloric acid (1 mL), and the mixture was stirred at 80°C for 2.5 hrs. The reaction mixture was diluted with ethyl acetate (80 mL) and washed with aqueous sodium hydrogen carbonate (30 mL). The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue, 2-(methylsulfonyl)acetic acid (207 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (429 mg), 1-hydroxybenzotriazole monohydrate

15 (304 mg), triethylamine (0.697 mL) and N,N-dime1hylformamide (7.69 mL) were reacted in the same manner as in Synthesis Example 155 (iv). The obtained compound was treated with 4N hydrochloric acid/ethyl acetate to give the title compound (149 mg) as colorless crystals. 1H-NMR (DMSO-de) δ 3.02 (3H, s), 3.20 (2H, s), 3.51 (2H, m), 3.71 (3H, s), 3.90 (2H, s), 6.72 (IH, d, J= 3 Hz), 7.2-7.4 (4H, m), 7.52 (IH, d, J= 8 Hz), 7.68 (2H, m), 7.86 (IH, d, J= 2 Hz), 8.40 (IH, 0 m), 8.94 (IH, s). Synthesis Example 208

Production of N-[2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyiitnidin- 5-yl)ethyl]-3-hydroxy-3-mefhylbutanamide The title compound (145 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]- 5H-pyiτolo[3,2-d]pyrirnidin-4-arnine dihydrochloride (200 mg) and 3-hydroxy-3-methylbutyric acid (104 mg).

¹H-NMR (CDCl₃) δ: 1.33 (6H, s), 2.49 (2H, s), 3.55-3.7 (2H, m), 4.4-4.55 (2H, m), 6.60 (IH, d, J= 3.4 Hz), 6.85-7.1 (4H, m), 7.1-7.3 (2H, m), 7.7-7.8 (IH, m), 8.05 (IH, d, J- 2.6 Hz), 8.52 (IH, s), 8.64 (IH, s).

Synthesis Example 209

Production of N-{2-[4-({3-cMoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl} -2-(isopropylsulfonyl)acetamide 5-(2-Ammoelhyl)-N-{3-cMoro4-[3-(tiffluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (300 mg) and 4-methylmorpholine (3.0 mL) were dissolved in tetrahydrofuran (7.0 mL), chloroacetyl chloride (0.7 mL) was added, and the mixture was stirred at 0⁰C for 2 hrs. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate 5 under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was dissolved in a mixed solvent of N₅N- dimethylformarnide (3.5 mL) and tetrahydrofuran (6.0 mL). To the mixture was added sodium 2- methylpropane-2-thiolate (180 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling i o and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -> ethyl acetate:methanol=90: 10) to give an oil. The title compound (165 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 172 (ii) using the oil obtained above and titanium tetraisopropoxide (0.15 mL), methanol is (0.52 mL) and 70% aqueous tert-butyl hydroperoxide solution (12.0 mL).

¹H-NMR (DMSOd₆) δ: 1.24 (6H, d, J= 6.8 Hz), 3.45-3.58 (3H, m), 4.03 (2H, s), 4.56 (2H, m), 6.52 (IH, m), 7.20-7.99 (8H, m), 8.35 (IH, s), 8.72 (IH, s). Synthesis Example 210

Production of N-{2-[4-({3-cUoro-4-[3-(1rifluorome1hyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- dJpyrimidin-S-ylJethylJ^-Kcyclopenty^sulfonylJacetaEnide

The title compound (115 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 209 using 5-(2-aminoethyl)-N-{3-chloro-4-[3-

(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirrύdin-4-amine dihydrochloride (350 mg), 4-methylmorpholine (3.50 mL), chloroacetyl chloride (0.9 mL), sodium cyclopentanethiolate (890 mg), titanium tetraisopropoxide (0.25 mL), methanol (0.55 mL) and 70% aqueous tert-butyl hydroperoxide solution (15.0 mL). 1H-NMR (DMSOd₆) δ: 1.50-1.63 (4H, m), 1.89 (4H, m), 3.47 (2H, m), 3.79 (IH, m), 3.99 (2H, s), 4.56 (2H, m), 6.52 (IH, m), 7.20-7.99 (8H, m), 8.35 (IH, s), 8.72 (IH, s).

Synthesis Example 211

Production ofN-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5-[2-(2,2,2- Mfluoroe1hoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidin-4-amine The title compound (175 mg) was obtained as crystals by the reaction in the same manner as in Synthesis Example 171 using 4-cMoro-5H-pyrrolo[3,2-d]pyrimidine (340 mg), potassium carbonate (530 mg) and 2-(2,2,2-trifluoroethoxy)ethyl methanesulfonate (550 mg). 1H-NMR (DMSO-d_δ) δ: 3.91-4.09 (4H, m), 3.73-3.76 (2H, m), 6.53 (IH, d, J= 3 Hz), 7.21-7.92 5 (8H, m), 8.36 (IH, s), 8.62 (IH, s).

Synthesis Example 212

Production of (2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H- pyrrolo[3,2-d]pyrirnidm-6-yl)prop-2-en-l-yl]-4-(dimethylamino)but-2-enamide i o (i) Production of N-(4,6-ά^odopyrimidin-5-yl)-2,2,2-trifluoro-N-methylacetamide

4,6-Dnodopyrimidin-5-amine (20 g) was dissolved in dichloromethane (200 mL), and trifluoroacetic anhydride (47.3 mL) and triethylamine (8.04 mL) were successively added dropwise. The mixture was stirred at room temperature for 1 hr, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (150 mL), and concentrated again

15 under reduced pressure to give a colorless solid. The obtained solid was dissolved in N₅N- dimethylformamide (106 mL), potassium carbonate (15.9 g) and iodomethane (10.8 mL) were added, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with diethyl ether (400 mL) and washed with water (400 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (25.1 g) as a 0 colorless solid. ¹H-NMR (CDCl₃) δ: 3.34 (2H, s), 3.48 (IH, s), 8.44 (IH, d, J= 2 Hz).

(ii) Production of N-(4-{[3-cMoro4-(3-cyanophenoxy)phenyl]ammo}-6-iodopyrimidin-5-yl)-2,2,2- trifluoro-N-raethylacetamide

N-(4,6-DModopyrimidin-5-yl)-2,2_>2-trifluoro-N-methylacetamide (3 g) and 3-(4-amino-2- 5 chlorophenoxy)benzonitrile (1.69 g) were dissolved in 1 -methyl-2-pyrrolidone (11.4 mL), and the mixture was stirred with heating at 100⁰C for 16 hrs. To the reaction mixture was added aqueous sodium hydrogen carbonate (80 mL) and the mixture was extracted with ethyl acetate (100 mLx2).

The organic layer was washed with saturated brine (80 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column i o chromatography (eluent, hexane:ethyl acetate=90: 10 -» hexane:ethyl acetate=50:50) and crystallized from dϋsopropyl ether to give the title compound (1.67 g) as colorless crystals.

¹H-NMR (CDCl₃) δ: 3.39 (3H, s), 7.1-7.6 (6H, m), 7.90 (IH, d, J= 3 Hz), 8.37 (IH, s).

(iϋ) Production of 3-(2-cMoro-4-{[6-iodo-5-(memylamino)pyrimidin-4- yl]amino}phenoxy)benzonitrile is To a solution of N-(4-{[3-cMoro4-(3-cyanophenoxy)phenyl]amino}-6-iodopyrimidin-5- yl)-2,2,2-trifiuoro-N-methylacetamide (1.0 g) in isopropanol-tetrahydrofuran (5.0 mL-10 mL) was added sodium borohydride (70 mg) at room temperature. The mixture was stirred at room temperature for 1.5 hrs, and ethyl acetate was added. The mixture was washed with water and saturated brine and the organic layer was dried over magnesium sulfate. After concentration under 0 reduced pressure, the residue was separated and purified by silica gel column chromatography

(eluent, hexane:ethyl acetate=4:l —> 3:2) to give the title compound (755 mg) as a white amorphous solid.

¹H-NMR (CDCl₃) δ: 2.72 (3H, d, J= 6.3 Hz), 2.86-2.98 (IH, m), 7.15-7.21 (3H, m), 7.31-7.45 (2H, m), 7.58 (IH, dd, J= 9.0, 2.7 Hz), 7.73 (IH, br s), 7.99 (IH, d, J= 2.7 Hz), 8.20 (IH, s).

(iv) Production of tert-butyl {(2E)-5-[6-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-

(me1hylairtino)pyrimidin-4-yl]pent-2-en-4-yn- 1 -yl} carbamate

The title compound (366 mg) was obtained as brown powder crystals by the reaction in the same manner as in Synthesis Example 81 (ii) using 3 -(2-chloro-4- { [6-iodo-5-

(memylamino)pyrirmdin4-yl]amino}phenoxy)benzonitrile (755 mg), tert-butyl pent-2-en-4- ynylcarbamate (0.43 g), bis(triphenylphosphine)palladium(II) dichloride (55.5 mg), copper(T) iodide

(18 mg), acetonitrile (16 mL) andtriethylamine (12 mL).

¹H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.78 (3H, d, J= 6.3 Hz), 3.15-3.27 (IH, m), 3.84-3.95 (2H, m), 4.53-4.65 (IH, m), 5.84-5.93 (IH, m), 6.34-6.43 (IH, m), 7.09 (IH, d, J= 8.7 Hz), 7.10-7.22 (2H, m), 7.32-7.44 (2H, m), 7.55 (IH, br s), 7.59 (IH, dd, J= 8.7, 2.7 Hz), 7.99 (IH, d, J= 2.7 Hz), 8.46

(IH, s).

(v) Production of tert-butyl [(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]arnino}-5-methyl-

5H-pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-l-yl]carbamate The title compound (200 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 81 (iii) using tert-butyl {(2E)-5-[6-{[3-chloro-4-(3- cyanophenoxy)phenyl]amino} -5-(me1faylamino)pyrimidin-4-yl]pent-2-en-4-yn- 1 -yl} carbamate

(366 mg), copper(T) iodide (13 mg) andN,N-dimethylformamide (4.0 mL).

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 3.92-4.03 (5H, m), 4.714.86 (IH, m), 6.31-6.45 (IH, m), 6.56 (IH, d, J= 15.9 Hz), 6.67 (IH, s), 6.74 (IH, s), 7.06-7.22 (3H, m), 7.31-7.46 (3H, m), 7.75 (IH, d, J=

2.7 Hz), 8.49 (IH, s).

(vi) Production of 3-[4-({6-[(lE)-3-ammoprop-l-en-l-yl]-5-methyl-5H-pyrrolo[3,2-d]pyiitrιidin-4- yl} amino)-2-chlorophenoxy]benzonitrile dihydrochloride The title compound (170 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 81 (iv) using tert-butyl [(2E)-3-(4-{[3-chloro-4-(3- cyanophenoxy)phenyl]arnino}-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-6-yl)prop-2-en-l- yl]carbamate (190 mg), 2N hydrochloric acid (4.5 rriL) and tetrahydrofuran (9.0 mL). 5 ¹H-NMR (DMSOd₆) δ: 3.75 (2H, t, J= 5.3 Hz), 4.17 (3H, s), 6.62-6.72 (IH, m), 6.87 (IH, s), 7.13 (IH, d, J= 16.5 Hz), 7.25-7.34 (2H, m), 7.43-7.46 (IH, m), 7.55-7.67 (3H, m), 7.93 (IH, d, J= 2.4 Hz), 8.16-8.31 (3H, m), 8.64 (IH, s), 9.83 (IH, br s).

(vϋ) Production of (2E)-N-[(2E)-3-(4-{[3-chloro-4-(3-cyanophenoxy)phenyl]amino}-5-methyl-5H- pyrrolo [3 ,2-d]pyrimidin-6-yl)prop-2-en- 1 -yl] -4-(dimethylamino)but-2-enamide i o The title compound (74 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 82 using 3-[4-({6-[(lE)-3-aminoprop-l-en-l-yl]-5-methyl- 5H-pyrrolo[3,2-d]pyrirrddin-4-yl}amino)-2-cUorophenoxy]benzonitrile dihydrochloride (160 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (182 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (420 mg), 1-hydroxybenzotriazole monohydrate

15 (340 mg), triethylamine (0.80 mL) andN,N-cUme1hylformamide (5.0 mL).

¹H-NMR (DMSOd₆) δ: 2.15 (6H, s), 3.00 (2H, dd, J= 6.0, 1.2 Hz), 3.95-4.08 (5H, m), 6.05-6.14 (IH, m), 6.42-6.53 (IH, m), 6.60 (IH, dt, J= 15.6, 6.6 Hz), 6.72 (IH, s), 6.78 (IH, d, J= 15.6 Hz), 7.20-7.28 (2H, m), 7.39-7.43 (IH, m), 7.53-7.59 (2H, m), 7.60-7.68 (IH, m)₅7.68-7.92 (IH, m), 8.28 (IH, s), 8.32 (IH, t, J= 5.4 Hz), 8.77 (IH, s). 0 Synthesis Example 213

Production of (2E)-N-{[4-({3-cUoro4-[3-(1xifluoromethoxy)phenoxy]phenyl}amino)-5-me1liyl-

5H-pyrrolo[3,2-d]pyrimidin-6-yl]me1hyl}-4-(^^

(i) Production of 4,6-duodo-N-me1hylpyrimidin-5-amine 5 To a solution of 4,6-diiodopyrimidin-5-amine (1.0 g) in tetrahydrofuran (10 rriL) was added sodium hydride (60%, 138 mg) under ice-cooling. The mixture was stirred at room temperature for

30 min. To the reaction system was added dropwise a solution of methyl methanesulfonate (0.256 mL) in tetrahydrofuran (4.0 mL). The mixture was stirred at room temperature for 3 hrs and ethyl acetate was added. The mixture was washed with water and saturated brine and dried over i o magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=9:l -> 3:1) to give the title compound (600 mg) as pale-yellow crystals.

¹H-NMR (CDCl₃) δ: 3.02 (3H, d, J= 5.7 Hz), 3.71-3.83 (IH, m), 8.04 (IH, s).

(ii) Production of N4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N5- 15 methylpyrimidine-4,5-ctøamine

The title compound (552 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 212 (ii) using 4,6-diiodo-N-methylpyrirrήdin-5-amine (600 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]anUine (504 mg) and l-methyl-2-pyrrolidone (10 mL). 0 ¹H-NMR (DMSOd₆) δ: 2.71 (3H, d, J= 5.7 Hz)₃2.87-2.98 (IH, m), 6.76-6.85 (2H, m), 6.90-6.96 (IH, m), 7.09 (IH, d, J= 8.7 Hz), 7.29-7.34 (IH, m), 7.52-7.56 (IH, m), 7.70 (IH, br s), 7.96 (IH, d,

J= 1.5 Hz), 8.19 (IH, s).

(iϋ) Production of tert-butyl {[4-({3-cUoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}aπώio)-5- me&yl-5H-pyrrolo[3,2-d]pyrimidin-6-yl]me1hyl}carbamate 5 To a solution of N4-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-6-iodo-N5- me1hylpyrimidine-4,5-diarnine (1.53 g), tert-butyl piOp-2-ynylcarbamate (0.67 g) and triethylamine

(1.19 mL) in acetonitrile (28 mL) were added bis(triphenylphosphine)palladium(ll) dichloride (100 mg) and copper(T) iodide (32.5 mg) at room temperature. Under an argon atmosphere, the mixture was stirred at room temperature for 4.5 hrs, heated at 50⁰C, and the mixture was stirred for 6 hrs. i o After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate^:=7:3 — » 3:7 — » basic silica gel, hexane:ethyl acetate=l : 1 -» ethyl acetate) to give the title compound (1.05 g) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.48 (9H, s), 4.04 (3H, s), 4.52 (2H, d, J= 6.0 Hz), 4.83-4.95 (IH, m), 6.49 (IH, s), 6.76-6.96 (4H, m), 7.08 (IH, d, J= 8.7 Hz), 7.31 (IH, t, J= 8.3 Hz), 7.43 (IH, dd, J= 8.3 Hz), 7.78 is (IH, d, J= 2.4 Hz), 8.48 (IH, s).

(iv) Production of 6-(aminomemyl)-N-{3-cMoro4-[3-(trifluoromethoxy)phenoxy]phenyl}-5- me1hyl-5H-pyrrolo[3,2-d]pyrirmdin-4-amine dihydrochloride

The title compound (1.01 g) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 81 (iv) using tert-butyl {[4-({3-chloro-4-[3- 0 (1ruluorome1hoxy)phenoxy]phenyl}ammo)-5-memyl-5H-pyrrolo[3,2-d]pyrirmdin-6- yl]methyl} carbamate (1.05 g), 2N hydrochloric acid (20 mL) and tetrahydrofuran (40 mL).

¹H-NMR (DMSOd₆) δ: 4.18 (3H, s), 4,39-4.48 (2H, m), 6.89 (IH, s), 6.94-6.99 (2H, m), 7.15 (IH, d, J= 9.0 Hz), 7.35 (IH, d, J= 8.7 Hz), 7.50-7.56 (IH, m), 7.67 (IH, dd, J= 9.0, 2.4 Hz), 7.94 (IH, d, J= 2.4 Hz), 8.72 (IH, s), 8.77-8.92 (3H, m), 10.04 (IH, br s).

(v) Production of (2E)-N-{[4-({3-cMoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}airiino)-5- me&yl-5H-pyrrolo[3,2-d]pyrirnidm-6-yl]m

The title compound (105 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 82 using 6-(aminomethyl)-N-{3-chloro4-[3- (trMuoromethoxy)phenoxy]phenyl}-5-me1hyl-5H-pyrrolo[3,2-d]pyrimidm-4-amine dihydrochloride (200 mg), (2E)-4-(dimethylamino)but-2-enoic acid hydrochloride (124 mg), 1- ethyl-3-(3-dime1liylaminopropyl)carbodiirnide hydrochloride (214 mg), 1-hydroxybenzotriazole monohydrate (171 mg), triethylamine (0.52 mL) andN,N-dimethylformamide (5.0 mL). 1H-NMR (CDCl₃) δ: 2.14 (6H, s)_s 3.00 (2H, d, J= 6.3 Hz), 4.00 (3H, s), 4.58 (2H, d, J= 5.4 Hz), 6.11 (IH, d, J= 15.3 Hz), 6.39 (IH, s), 6.58-6.68 (IH, m), 6.87-6.95 (2H, m), 7.04-7.11 (IH, m), 7.25 (IH, d, J= 8.7 Hz), 7.45-7.51 (IH, m), 7.60-7.68 (IH, m), 7.91 (IH, d, J= 2.7 Hz), 8.28 (IH, s), 8.54-8.61 (IH, m), 8.71 (IH, s). Synthesis Example 214

Production of N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl} -3-hydroxy-2,2-dimethylpropanamide hydrochloride

A solution of 5-(2-ammoethyl)-N-{3-chloro-4-[3-(trifluorome1hyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amme dihydrochloride (150 mg), 3-hydroxy-2,2-dimethylpropanoic acid (68 mg), l-e1hyl-3-(3-dime1hylaminopropyl)carbodiitnide hydrochloride (166 mg), 1- hydroxybenzotriazole monohydrate (132 mg) and triethylamine (0.40 mL) in N₅N- dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed 5 with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate — » methanol:e1hyl acetate=15:85). After concentration under reduced pressure, ethyl acetate (2.0 mL) and 4N hydrochloric acid/ethyl acetate (0.5 mL) were added, and the mixture was stirred at room temperature for 15 hrs. After concentration under reduced pressure, the i o precipitated crystals were collected by filtration. To a solution of the collected crystals in ethanol (2.0 mL) was added IN aqueous sodium hydroxide solution at room temperature, and the mixture was stirred for 2 days. The mixture was concentrated under reduced pressure and a solution of the residue in ethyl acetate was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, 4N hydrochloric acid/ethyl acetate (0.5 mL)

15 was added to a solution of the residue in ethyl acetate (1.0 mL). After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (119 mg) as colorless crystals. 1H-NMR (DMSOd₆) δ: 0.96 (6H, s), 3.23-3.52 (4H, m), 4.56-4.68 (2H, m), 6.64 (IH, d, J= 3.0 Hz), 7.23-7.30 (2H, m), 7.38 (IH, d, J= 8.4 Hz), 7.52 (IH, d, J- 8.1 Hz), 7.61-7.69 (IH, m), 7.72-7.80 0 (IH, m), 7.85-7.92 (2H, m), 8.00-8.03 (IH, m), 8.70 (IH, s), 9.95-10.06 (IH, m). Synthesis Example 215

Production of N-{2-[4-({3-cMoro4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethyl}-2-(methylsulfonyl)propanamide

To arnixtøe of 5-(2-anmoe1hyl)-N-{3-cM^ 5 pyrrolo[3,2-d]pyrirnidin-4-amine dihydrochloride (150 mg), trieihylamine (0.39 mL) and tetrahydrofuran (5.0 mL) was added 2-chloropropionyl chloride (54 μL) at room temperature. The mixture was stirred at room temperature for 3 days, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, sodium methanesulfinate (85 mg) and pyridine i o (67 μL) were added to a solution of the residue in N,N-dimethylformamide (5.0 mL), and the mixture was stirred at 70⁰C for 2 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate -» ethyl

15 acetate:methanol=9 : 1 ) and recrystallized from ethyl acetate-diisopropyl ether to give the title compound (114 mg) as colorless crystals.

¹H-NMR (CDCl₃) δ: 1.71 (3H, d, J= 7.2 Hz), 2.98 (3H, s), 3.63-3.75 (2H, m), 3.81 (IH, q, J= 7.2 Hz), 4.444.55 (2H, m), 6.64 (IH₅ d, J= 3.0 Hz), 7.09 (IH, d, J= 8.7 Hz), 7.11-7.18 (2H, m), 7.19- 7.25 (2H, m), 7.30-7.36 (IH, m), 7.40-7.47 (IH, m), 7.85 (IH, dd, J= 8.7, 2.7 Hz), 8.01 (IH, d, J= 2.7 Hz), 8.30 (IH, s), 8.54 (IH, s).

Synthesis Example 216

Production of N-{2-[4-({3-cMoro4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide

The title compound (128 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro4-[3- (trMuoromethyl)phenoxy]phenyl}-5H-pyirolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), 2-hydroxy-2-(trifluoromethyl)propionic acid (88.2 mg), l-ethyl-3-(3- dimetiiylaminopropyl)carbodiirnide hydrochloride (160 mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine (0.39 mL) and N,N-dimethylformamide (5.0 mL). 1H-NMR(CDCl₃) δ: 1.68 (3H, s), 3.65-3.77 (2H, m), 3.80-3.89 (IH, m), 4.434.57 (2H, m), 6.63 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.11-7.16 (IH, m), 7.19-7.28 (3H, m), 7.30-7.36 (IH, m), 7.40-7.43 (IH, m), 7.79 (IH, dd, J= 8.7, 2.4 Hz), 8.08 (IH, d, J= 2.4 Hz), 8.31 (IH, s), 8.53 (IH, s). Synthesis Example 217

Production of N-{2-[4-({3-cMoro4-[3-(trifluorome1hyl)phenoxy]phenyl}animo)-5H-pyrrolo[3,2- d]pyritnidin-5-yl]ethyl} -2-(methylsulfonyl)acetamide 4-methylbenzenesulfonate

To a solution of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidin-5-yl]e1hyl}-2-(methylsulfonyl)acetarnide (150 mg) in ethyl acetate (10 mL) was added 4-methylbenzenesulfonic acid monohydrate (55.4 mg) at room temperature. The mixture was stirred at room temperature for 20 hrs, and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration and washed with ethyl acetate and diisopropyl ether to give the title compound (150.3 mg) as colorless crystals. 1H-NMR (DMSOd₆) δ: 2.29 (3H, s), 3.07 (3H, s), 3.44-3.60 (2H, m), 4.06 (2H, s), 4.61-4.70 (2H, m), 6.66 (IH, d, J= 3.0 Hz), 7.11 (2H, d, J- 8.4 Hz), 7.22-7.28 (2H, m), 7.38 (IH, d, J= 8.7 Hz), 7.47 (2H, d, J= 8.4 Hz), 7.50-7.55 (IH, m), 7.62-7.72 (2H, m), 7.89-7.96 (2H, m), 8.65-8.74 (2H, m), 9.70-9.80 (IH, m). Synthesis Example 218

Production of N-{2-[4-({3-cUoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]e1hyl} -2-(methylsulfonyl)acetamide hydrochloride

The title compound (147 mg) was obtained as colorless crystals in the same manner as in Synthesis Example 217 using N-{2-[4-({3-cUoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)- 5 SH-pyrroloP^-d^yrimidin-S-yyethylJ^-^ethylsutfony^acelamide (150 mg), 4N hydrochloric acid/ethyl acetate (0.13 mL) and ethyl acetate (10 mL).

¹H-NMR (DMSOd₆) δ: 3.06 (3H, s), 3.35-3.59 (2H, m), 4.07 (2H, s), 4.63-4.74 (2H, m), 6.67 (IH, d, J= 3.0 Hz), 7.25-7.30 (2H, m), 7.38 (IH, d, J= 8.7 Hz), 7.51-7.54 (IH, m), 7.62-7.72 (2H, m), 7.92-7.99 (2H, m), 8.70-8.79 (2H, m), 9.78-9.89 (IH, m). i o Synthesis Example 219

Production of N-{2-[4-({3-cUoro-4-[3-(1rMuoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl} -2-(me1hylsulfonyl)acetarnide methanesulfonate

The title compound (1,14 g) was obtained as colorless crystals in the same manner as ins Synthesis Example 217 using N-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]ρhenyl}amino)- 5H-pyrrolo[3,2-d]pyrimidin-5-yl]emyl}-2-(methylsuh^conyl)acetamide (1.0 g), methanesulfonic acid (0.126 mL) and ethyl acetate (50 mL).

¹H-NMR (DMSOd₆) δ: 2.30 (3H, s), 3.06 (3H, s), 3.47-3.61 (2H, m), 4.06 (2H, s), 4.63-4.72 (2H, m), 6.67 (IH, d, J= 3.3 Hz), 7.23-7.29 (2H₅ m), 7.37-7.40 (2H, m), 7.63-7.73 (2H, m), 7.91-7.98 (2H, m), 8.68-8.78 (2H, m), 9.80 (IH, br s).

Synthesis Example 220

Production of N-{2-[4-({3-cWoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- 5 d]pyrimidin-5-yl]- 1 -methylethyl} -2-(methylsulfonyl)acetamide

(i) Production of tert-butyl [2-(4-cWoro-5H-pyrrolo[3,2-d]pyrirrύdin-5-yl)-l-methylethyl]carbamate

To a solution of 2-aminopropan-l-ol (1.0 g) intetrahydrofuran (50 mL) was added di-tert- butyl dicarbonate (3.1 mL) at room temperature. The mixture was stirred at room temperature for 3 days and concentrated under reduced pressure. To a solution of the residue and triethylamine (3.7 i o mL) in tetrahydrofuran (30 mL) was added methanesulfonyl chloride (1.54 mL) under ice-cooling, and the mixture was stirred at 30 rnin. To the reaction system was added aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, A- cUoro-5H-pyrrolo[3,2-d]pyrimidine (1.02 g), cesium carbonate (6.49 g) andN,N-

15 dimethylformamide (10 mL) were added to the residue, and the mixture was stirred at 4O⁰C for 3 days. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=3 : 1 →- 2:3) to give the title compound (1.16 g) as a pale-yellow oil.

¹H-NMR (CDCl₃) δ: 0.93-1.35 (12H, m), 4.024.18 (1.5H, m), 4.39-4.53 (1.5H, m), 4.57-4.70 (IH, m), 6.74 (IH, d, J= 3.0 Hz), 7.50 (IH, d, J= 3.0 Hz), 8.71 (IH, s).

(ii) Production of 5-(2-aniinopropyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- 5 pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride

A solution of tert-butyl [2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)-l- methylethyi]carbarnate (350 mg) and 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (423 mg) in l-methyl-2-pyrrolidone (3.5 mL) was stirred at 12O⁰C for 4 hrs. After cooling to room temperature, triethylamine (0.24 mL) and di-tert-butyl dicarbonate (0.13 mL) were added, and the mixture was j o stirred for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. The residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=19:l -> 3:2 -> ethyl acetate) to give a brown solid. To a solution of the obtained solid in tetrahydrofuran (20 mL) was added 2N hydrochloric acid (10 mL) at room temperature, and the

15 mixture was stirred at 60°C for 20 hrs. After concentration under reduced pressure, ethanol was added and the mixture was further concentrated. To the residue was added dϋsopropyl ether, and the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (225 mg) as pale-yellow crystals. 1H-NMR (DMSO-dδ) δ: 1.17 (3H, d, J= 6.6 Hz), 3.35-3.77 (IH, m), 4.75-4.89 (IH, m), 4.98-5.09 0 (IH, m), 6.75 (IH, d, J= 2.7 Hz), 7.23-7.30 (2H, m), 7.37 (IH, d, J= 8.7 Hz), 7.52-7.54 (IH, m), 7.64-7.69 (2H, m), 7.89-7.97 (IH, m), 8.04-8.10 (IH₅ m), 8.24-8.43 (3H, m), 8.74 (IH, s), 10.04 (lH, br s).

(iii) Production of N-{2-[4-({3-cMoro4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirrήdm-5-yl]-l-methyle^

The title compound (34 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminopropyl)-N-{3-chloro-4-[3- (1rifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirrddm-4-arrώie dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (77 mg), l-emyl-3-(3-dimethylammopropyl)carbodiirnide hydrochloride (160 mg), 1-hydroxybenzotriazole monohydrate (128 mg), triethylamine (0.39 mL) andN,N-dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 1.28 (3H, d, J= 6.6 Hz), 3.14 (3H, s), 3.71-3.80 (IH, m), 4.00 (2H, s), 4.12- 4.26 (IH, m), 4.98-5.04 (IH, m), 6.62 (IH, d, J- 3.3 Hz), 6.82-6.88 (IH, m), 7.07 (IH, d, J= 8.7 Hz), 7.12-7.24 (3H, m), 7.30-7.35 (IH, m), 7.41-7.49 (IH, m), 7.79 (IH, dd, J= 8.7, 2.7 Hz), 7.95 (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.54 (IH, br s). Synthesis Example 221

Production of N-{2-[4-({3-cMoro-4-[3-(1rMuoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirmdm-5-yl]ethyl}-3-hydroxy-3-meth.ylbutanamide methanesulfonate

To a solution of N-{2-[4-({3-cMoro-4-[3-(1rrfluoromemyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidm-5-yl]ethyl}-3-hydroxy-3-me1hylbutanarnide (200 mg) in ethyl acetate (10 mL) was added methanesulfonic acid (26 μL) at room temperature. The mixture was stirred at room temperature for 1 hr and concentrated under reduced pressure. To the residue were added ethanol and ethyl acetate, and the precipitated crystals were collected by filtration to give the title compound (223 mg) as colorless crystals.

¹H-NMR (DMSOd₆) δ: 1.12 (6H, s), 2.21 (2H, s), 2.29 (3H, s), 3.41-3.54 (2H, m), 4.56-4.68 (2H, m), 6.66 (IH, d, J= 3.3 Hz), 7.26-7.28 (2H, m), 7.37 (IH, d, J= 9.0 Hz), 7.51-7.54 (IH, m), 7.61- 5 7.75 (2H, m), 7.95-8.03 (2H, m), 8.31-8.40 (IH, m), 8.72 (IH, s), 10.11-10.19 (IH, m). Synthesis Example 222

Production of N-{2-[4-({3-cWoro-4-[3-(1iMuoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirrddin-5-yl]ethyl}-N-ethyl-2-(me1hylsu]fonyl)acetamide i o (i) Production of tert-butyl [2-(4-cWoro-5H-pyrrolo[3,2-d]pyrirmdin-5-yl)e1hyl]ethylcarbamate

The title compound (630 mg) was obtained as a pale-yellow oil by the reaction in the same manner as in Synthesis Example 163 (i) using 2-(ethylamino)ethanol (1.00 g), di-tert-butyl dicarbonate (2.58 mL), terrahydrofuran (100 mL), methanesulfonyl chloride (1.30 mL), triethylamine (3.12 mL), tetrahydrofuran (50 mL), 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.86 g), is cesium carbonate (7.5 g) and N,N-dimethylformamide (20 mL).

¹H-NMR (CDCl₃) δ: 0.84-1.48 (12H, m), 2.80-2.93 (IH₅ m), 3.07-3.22 (IH, m), 3.51-3.67 (2H, m),

4.52-4.72 (2H, m), 6.73 (IH, d, J= 3.3 Hz), 7.29-7.47 (IH, m), 8.71 (IH, s).

(ii) Production of tert-butyl {2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrirnidin-5-yl]ethyl}ethylcarbamate The title compound (950 mg) was obtained as a colorless solid by the reaction in the same manner as in Synthesis Example 155 (ϋ) using tert-butyl [2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-

5-yl)ethyl]ethylcarbamate (630 mg), 3-cMoro-4-[3-(tiffluoromethyl)phenoxy]aniline (725 mg) and isopropyl alcohol (6.0 mL). 1H-NMR (CDCl₃) δ: 1.18 (3H, t, J= 7.2 Hz), 1.52 (9H, s), 3.35 (2H₅ q, J= 7.2 Hz), 3.49-3.58 (2H, m), 4.41-4.51 (2H, m), 6.60 (IH, d, J= 3.0 Hz), 7.07 (IH, d, J= 9.0 Hz), 7.09-7.15 (IH, m), 7.18-

7.22 (2H, m), 7.29-7.33 (IH, m), 7.39-7.45 (IH, m), 7.93 (IH, d, J= 9.0, 2.4 Hz), 8.04 (IH, d, J= 2.4

Hz), 8.51 (IH, s), 8.92 (IH, br s).

(iii) Production of N-{3-cUoro4-[3-(tήfluoromethyl)phenoxy]phenyl}-5-[2-(e1hylamino)ethyl]- 5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride

The title compound (861 mg) was obtained as pale-yellow crystals by the reaction in the same manner as in Synthesis Example 155 (iii) using tert-butyl {2-[4-({3-chloro-4-[3-

(trifluoromethyl)phenoxy]phenyl}amino)-5H^^

(950 mg), 2N hydrochloric acid (5.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSOd₆) δ: 1.18 (3H, t, J= 7.5 Hz), 2.89-3.02 (2H, m), 3.33-3.47 (2H, m), 5.03-5.12

(2H, m), 6.72-6.77 (IH, m), 7.22-7.29 (2H, m), 7.37 (IH, d, J= 9.0 Hz), 7.51-7.54 (IH, m), 7.61-

7.71 (2H, m), 7.91-7.98 (IH, m), 8.04-8.10 (IH, m), 8.72 (IH, s), 9.05-9.21 (2H, m), 9.95-10.05

(IH, m).

(iv) Production of N-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo[3,2-d]pyrirrύdin-5-yl]ethyl}-N-ethyl-2-(methylsulfonyl)acetamide

The title compound (94 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3-

(1rifluoromethyl)phenoxy]phenyl}-5-[2-(e^ dihydrochloride (150 mg), 2-(methylsulfonyl)acetic acid (76 mg), l-ethyl-3~(3- dimethylarninopropyl)carbodiimide hydrochloride (158 mg), 1-hydroxybenzotriazole monohydrate (126 mg), triethylamine (0.38 mL) andN,N-dime1hylformamide (5.0 mL). 1H-NMR(CDCl₃) δ: 1.36 (3H, t, J= 7.2 Hz), 3.20 (3H, s), 3.61 (2H, q, J= 7.2 Hz), 3.71-3.80 (2H, 5 m), 4.15 (2H, s), 4.45-4.53 (2H, m), 6.64 (IH, d, J= 3.3 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.10-7.17 (IH, m), 7.19-7.23 (2H, m), 7.30-7.35 (IH, m), 7.40-7.46 (IH, m), 7.89 (IH, dd, J= 8.7, 2.7 Hz), 7.96 (IH, d, J= 2.7 Hz), 8.53 (IH, s), 8.60 (IH, s). Synthesis Example 223

i o Production of N-{2-[4-({3-cMoro-4-[3-(Mfluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirmdin-5-yl]emyl}-N-e1hyl-3-hydroxy-3-methylbutariarnide

The title compound (106 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using N-{3-chloro-4-[3- (trrfluoromethyl)phenoxy]phenyl}-5-[2-(ethylarnmo)ethyl]-5H-pyrrolo[3,2-d]pyrim^ is dihydrochloride (150 mg), 3-hydroxy-3-methylbutyric acid (64.6 mg), l-ethyl-3-(3- dime1hylaminopropyl)carbodiirnide hydrochloride (157 mg), 1-hydroxybenzotriazole monohydrate (125 mg), triethylamine (0.38 mL) andN,N-dimethylformamide (5.0 mL). 1H-NMR (CDCl₃) δ: 1.29 (3H, t, J= 7.2 Hz), 1.34 (6H, s), 2.56 (2H, s), 3.47 (2H, q, J= 7.2 Hz), 3.65-3.75 (2H, m), 4.42-4.52 (3H, m), 6.62 (IH, d, J= 3.0 Hz), 7.08 (IH, d, J= 8.7 Hz), 7.10-7.15 (IH, m), 7.20 (IH, d, J= 3.0 Hz), 7.24-7.33 (2H, m), 7.39-7.46 (IH, m), 7.72 (IH, dd, J= 8.7, 2.4

Hz), 8.03 (IH, d, J= 2.4 Hz), 8.50 (IH, s), 8.81 (IH, s).

Synthesis Example 224

5 Production of N-{2-[4-({3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethyl}-2-(dimethylamino)acetarnide

The title compound (84 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-

(trMuorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (150 mg), i o N,N-dimethylglycine (59.4 mg), l-ethyl-3-(3-dime1hylaminopropyl)carbodiirnide hydrochloride

(166 mg), 1-hydroxybenzotriazole monohydrate (132 mg), triethylamine (0.40 mL) andN,N- dimethylformamide (5.0 mL).

¹H-NMR (CDCl₃) δ: 2.29 (6H, s), 3.05 (2H, s), 3.58-3.70 (2H, m), 4.45-4.54 (2H, m), 6.63 (IH, d,

J= 3.0 Hz), 7.08 (IH, d, J= 9.0 Hz), 7.10-7.15 (IH, m), 7.20 (IH, d, J= 3.0 Hz), 7.23-7.34 (2H, m), is 7.36-7.45 (IH, m), 7.70-7.79 (2H, m), 8.10 (IH, d, J= 2.7 Hz), 8.52 (IH, s), 8.63 (IH, s).

Synthesis Example 225

Production of N-{2-[4-({3-cWoro-4-[3-(trMuoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-methyl-l,3-oxazole-4-carboxamide

The title compound (112.1 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro4-[3-

(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirmdm-4-amine dihydrochloride (210 mg), 2-methyl-l,3-oxazole-4-carboxylic acid (210 mg), l-ethyl-3-(3-dimethylarninopropyl)carbodiirnide hydrochloride (560 mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSOd₆) δ 2.41 (3H, s), 3.56 (2H, m), 4.67 (2H, m), 6.53 (IH, d, J= 3 Hz), 7.21-7.91 (8H, m), 8.30 (IH, s), 8.42 (2H, m), 8.87 (IH, br s). Synthesis Example 226

Production of N-(2-{2-[4-({3-cMoro-4-[3-(trMuoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidm-5-yl]ethoxy}eth^^

© Production of 2-(2-{2-[4-({3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo [3 ,2-d]pyrirnidin-5-yl] ethoxy} ethyl)- 1 H-isoindole- 1 ,3 (2H)-dione The title compound (5.20 g) was obtained by the reaction in the same manner as in

Synthesis Example 172 (i) using 2-{2-[4-({3-cMoro-4-[3-(trrfluoromethyl)phenoxy]phenyl}arnino)- 5H-pyrrolo[3,2-d]pyrirnidin-5-yl]ethoxy}ethanol (4.00 g), tetrahydrofuran (25 mL), triethylamine (13.0 mL), methanesulfonyl chloride (7.25 mL), potassium phthalimide (4.51 g), tetrahydrofuran (60 mL) and N,N-dimethylformamide (50 mL). 1H-NMR (DMSO-de) δ 3.69 (4H₅ s), 3.83 (2H, m), 4.61 (2H, m), 6.33 (IH, m), 7.13-7.23 (3H, m), 7.42-7.95 (9H, m), 8.24 (IH, s), 8.75 (IH, s).

(ii) Production of N-(2-{2-[4-({3-cMoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]e1hoxy}e1hyl)-2,2,2-trifluoroe1hanesu]fonamide

2-(2-{2-[4-({3-CWoro-4-[3-(trifluorome%l)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethoxy}ethyl)-lH-isoindole-l,3(2H)-dione (100 mg) was dissolved in ethanol (2.0 mL), hydrazine monohydrate (0.45 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate:methanol^:=100:0 -» ethyl acetate:methanol=95:5). The obtained oil was dissolved in tetrahydrofuran (5.0 mL). N-Methylmoφholine (2.0 mL) was added, 2,2,2- trifiuoroethanesulfonyl chloride (0.10 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol^:=100:0 — > ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate gave the title compound (36.0 mg) as crystals. 5 ¹H-NMR (DMSO-dδ) δ 3.10 (2H, m), 3.47 (2H, m), 3.79 (2H, m), 4.30 (2H, m), 4.68 (2H, m), 6.52 (IH, m), 7.20-8.02 (9H, m), 8.35 (IH, s), 8.79 (IH, s). Synthesis Example 227

Production of N-{2-[4-({3-cMoro-4-[3-(Mfluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- i o d]pyrimidin-5-yl]ethyl} acetamide

The title compound (62.1 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-

(1rrfluorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-arnine dihydrochloride (270 mg), acetic acid (0.20 mL), l-e1hyl-3-(3-dimetiiylaminopropyl)carbodiirnide hydrochloride (500 mg), 1- 15 hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (10 mL).

¹H-NMR (DMSOd₆) δ 1.79 (3H, s), 3.37 (2H, m), 4.51 (2H, m), 6.51 (IH, d, J= 3 Hz), 7.20-7.81

(7H, m), 8.06 (IH, m), 8.26 (IH, m), 8.34 (IH, s), 8.81 (IH, s).

Synthesis Example 228

Production of N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}aniino)-5H- pyrrolo [3 ,2-d]pyrimidin-5-yl]ethoxy } ethyl)-2-(methylsulfonyl)acetamide hydrochloride

2-(2-{2-[4-({3-CMoro-4-[3-(trifluorome%l)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- 5 d]pyrirnidin-5-yl]ethoxy}ethyl)-lH-isoindole-l,3(2H)-dione (600 mg) was dissolved in ethanol (30 mL), hydrazine monohydrate (8.0 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by basic silica gel column chromatography i o (eluent, ethyl acetatemethanoMOOiO -» ethyl acetate:methanol^:=95:5). The title compound (312 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using the obtained oil, 2-(methylsulfonyi)acetic acid (500 mg), l-ethyl-3-(3- dimethylaminopropyl)carbodiirnide hydrochloride (1.50 g), 1-hydroxybenzotriazole monohydrate (200 mg), triethylamine (2.0 mL) andtetrahydrofuran (20 mL). is ¹H-NMR (DMSO-de) δ 3.06 (3H, s), 3.16-3.47 (4H, m), 3.81 (2H, m), 3.98 (2H, s), 4.86 (2H, s), 6.70 (IH, m), 7.25 - 7.68 (6H, m), 7.97-8.01 (2H, m), 8.44 (IH, m), 8.75 (IH, s), 9.90 (IH, s). Synthesis Example 229

Production of N-{2-[4-({3-cMoro-4-[3-(tiffluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-lH-pyrazole-3-carboxamide

The title compound (67.0 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro4-[3-

(trffluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (250 mg), lH-pyrazole-3-carboxylic acid (210 mg), l-e1hyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (500 mg), 1-hydroxybenzotriazole monohydrate (100 mg), triethylamine (2.0 mL) and tetrahydrofuran (15 mL). 1H-NMR (DMSOd₆) δ 3.58 (2H, m), 4.64 (2H, m), 6.49 (IH, m), 6.57 (IH, s), 7.21-7.79 (8H, m), 8.01 (IH, s), 8.33 (IH, s), 8.49 (IH, m), 8.77 (IH, s), 13.25 (IH, s). Synthesis Example 230

Production of (2R)-N-{2-[4-({3-cWoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}-2,3-clιhydroxypropanamide

The title compound (197.3 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirmdM-4-amine dihydrochloride (350 mg), (2R)-2,3-dihydroxypropanoic acid (400 mg), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.70 g), 1-hydroxybenzotriazole monohydrate (1.0 g), triethylamine (2.0 mL) and tetrahydrofbran (10 mL).

¹H-NMR (DMSO-d_δ) δ 3.33-3.58 (4H, m), 3.87 (IH, m), 4.53 (2H, m), 4.69 (IH, m), 5.62 (IH, d, J= 5 Hz), 6.48 (IH₃ d, J= 3 Hz), 7.20-7.81 (7H, m), 8.05 (IH, d, J= 2 Hz), 8.14 (IH, m), 8.34 (IH, s), 8.77 (IH, s). Synthesis Example 231

Production of N-(2-{2-[4-({3-cWoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyriniidin-5-yl]emoxy}e1hyl)memanesulfonamide

The title compound (18.2 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 226 (ii) using 2-(2-{2-[4-({3-chloro-4-[3- (trifluorome&yl)phenoxy]phenyl}amMo)-5H^^ isoindole-l,3(2H)-dione (200 mg), hydrazine monohydrate (1.50 mL), methanesulfonyl chloride (0.70 mL), N-methylmoφholine (1.20 mL), ethanol (7.0 mL) and tetrahydrofuran (10 mL). 1H-NMR (DMSO-d_δ) δ 2.78 (3H, s), 3.04 (2H, m), 3.48 (2H, m), 3.79 (2H, m), 4.68 (2H, m), 6.52 (IH, d, J= 3 Hz), 7.03-7.70 (8H, m), 8.02 (IH, s), 8.35 (IH, s), 8.81 (IH, s).

5 Synthesis Example 232

Production of N-(2-{2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}ethyl)acetamide

2-(2-{2-[4-({3-CUoro-4-[3-(trifluorome%l)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- i o d]pyrimidin-5-yl]ethoxy}ethyl)-lH-isoindole-l,3(2H)-dione (200 mg) was dissolved in ethanol (5.0 mL), hydrazine monohydrate (3.0 mL) was added, and the mixture was stirred for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate under ice-cooling and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by basic silica gel column chromatography is (eluent, ethyl acetate:methanol=100:0 -> ethyl acetatermethanoH^S). The title compound (146.0 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 180 using the obtained oil, acetic anhydride (1.0 mL), N-methylmorpholine (1.0 mL) and tetrahydrofuran (5.0 mL). ¹H-NMR (DMSOd₆) δ 1.69 (3H, s), 3.12 (2H, m), 3.44 (2H, m), 3.79 (2H₅ m), 4.66 (2H, m), 6.52 (IH, d, J= 3 Hz), 7.20-7.78 (8H, m), 8.00 (IH, s), 8.36 (IH, s), 8.85 (IH, s).

Synthesis Example 233

5 Production of N-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyiiιmαin-5-yl]ethyl}-N2-(methylsulfonyl)glycinamide

Using 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (450 mg), N-(tert-butoxy carbonyl)glycine (500 mg), l-e1hyl-3-(3-dimethylanτdnopropyl)carbodiimide hydrochloride (960 mg), 1- i o hydroxybenzotriazole monohydrate (300 mg), triethylamine (4.0 mL) and tetrahydrofuran (25 mL), the reaction was performed in the same manner as in Synthesis Example 155 (iv). The obtained compound was dissolved in methanol (5.0 mL), 4N hydrochloric acid/ethyl acetate (8 mL) was added, and the mixture was stirred for 5 hrs. 8N Aqueous sodium hydroxide solution (8 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane. The extract was

15 dried over magnesium sulfate and concentrated, and the residue was dissolved in tetrahydrofuran (5.0 mL). N-Methylmorpholine (1.0 mL) was added, methanesulfonyl chloride (0.70 mL) was added dropwise under ice-cooling, and the mixture was stirred for 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — > ethyl acetate:methanol=80:20), and crystallized from diethyl ether/ethyl 5 acetate to give the title compound (47.9 mg) as crystals.

¹H-NMR (DMSOd₆) δ 2.89 (3H, s), 3.46 (2H, m), 3.58 (2H, m), 4.54 (2H, m), 6.51 (IH, d, J= 3 Hz), 7.20-7.78 (8H, m), 8.02 (IH, s), 8.27 (IH, m), 8.36 (IH, s), 8.77 (IH, s).

Synthesis Example 234

i o Production of tert-butyl 4-(2-chloro-4-{[5-(2-{[(methylsulfonyl)acetyl]amino}ethyl)-5H- pvrrolo[3,2-d]pyrimidm-4-yl]amino}phenoxy)piperidine-l-carboxylate (i) Production of N-[2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]-2- (methylsulfonyl)acetamide tert-Butyl [2-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (300 mg) was

15 dissolved in trifluoroacetic acid (5.0 mL), and the mixture was stirred for 15 min. Toluene (5 mL) was added, the solvent was evaporated, and the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetatemethano^lOO÷O — » ethyl acetate:methanol=75:25). The title compound (64.0 mg) as colorless crystals were obtained by the reaction in the same manner as in Synthesis Example 155 (iv) using obtained oil, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (2.50 g), triethylamine (2.0 mL), 2- (methylsulfonyl)acetic acid (180 mg) andtetrahydrofuran (10 mL).

¹H-NMR (DMSOd₆) δ 3.07 (3H, s), 3.57 (2H, m), 4.00 (2H, s), 4.57 (2H, m), 6.74 (IH, d, J= 3 Hz), 7.92 (IH, d, J= 3 Hz), 8.49 (IH, m), 8.63 (IH, s). (ii) Production of tert-butyl 4-(2-cMoro4-{[5-(2-{[(me%lsulfonyl)acetyl]amino}ethyl)-5H- pyrrolo[3,2-d]pyrirnidin-4-yl]amino}phenoxy)piperidine-l-carboxylate

The title compound (24.0 mg) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 155 (ii) using N-[2-(4-cWoro-5H-pyrrolo[3,2-d]pyrirnidin-5- yl)ethyl]-2-(methylsulfonyl)acetarnide (60.0 mg) and tert-butyl 4-(4-amino-2- chlorophenoxy)piperidine-l-carboxylate (160 mg).

¹H-NMR (DMSOd₆) δ 1.41 (9H, s), 1.50-1.70 (2H, m), 1.81-1.95 (2H, m), 3.10 (3H, s), 3.22-3.60 (6H, m), 4.04 (2H, s), 4.45-4.65 (3H, m), 6.47 (IH, d, J= 3 Hz), 7.23 (IH, d, J= 9 Hz), 7.55-7.58 (2H, m), 7.75 (IH, d, J= 3 Hz), 8.27 (IH, s), 8.48 (IH, s), 8.66 (IH, m). Synthesis Example 235

Production of 3-[4-({3-cMoro-4-[3-(trffluoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- djpyrimidin-S-ylJ-N-P-^eihylsutfony^ethyypropanamide hydrochloride (i) Production of ethyl 3-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)propanoate

4-Chloro-5H-pyrrolo[3,2-d]pyrimidine (303 mg) was dissolved in N,N-dmemylformamide (9 mL), ethyl acrylate (0.3 mL) and potassium carbonate (538 mg) were sequentially added, and the mixture was stirred at room temperature for 7.5 hrs. Ethyl acrylate (0.2 mL) was added, and the mixture was stirred for 16 hrs. Ethyl acrylate (0.3 mL) and potassium carbonate (526 mg) were further added, and the mixture was stirred for 6 hrs. The reaction mixture was treated with saturated 5 aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=66:34 — > 20:80) to give the title compound (404 mg) as a colorless oil. i o ¹H-NMR (CDCl₃) δ: 1.22 (3H,t, J= 7.1 Hz),2.92 (2H,t, J- 6.3 Hz),4.13 (2H,q, J= 7.1 Hz),4.80 (2H,t, J= 6.3 Hz),6.70 (lH,d, J= 3.3 Hz),7.61 (IH, d, J= 3.3 Hz), 8.71 (lH,s). (ii) Production of ethyl 3-[4-({3-cMoro-4-[3-(ttMuorome1hyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]propanoate

The title compound (687 mg) was obtained as a pale-yellow oil by the reaction in the same

15 manner as in Synthesis Example 201 (iii) using ethyl 3-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)propanoate (404 mg), isopropyl alcohol (10 mL) and 3-chloro-4-[3- (trifluoromethyl)phenoxy]aniUne (555 mg).

¹H-NMR (CDCl₃) δ: 1.26 (3H,t, J= 7 Hz),2.99-3.10 (2H, m), 4.24 (2H, q, J= 7 Hz), 4.53-4.65 (2H_S m), 6.69 (lH,d,J= 3.3 Hz),7.06-7.17 (2H,m), 7.18-7.24 (IH, m), 7.27-7.35 (2H, m), 7.43 (lH,t, J= 0 7.9 Hz),7.65 (IH, dd, J= 8.8 Hz, 2.6 Hz), 7.92 (IH, d, J= 2.6 Hz), 8.54 (lH,s),9.14 (IH, s).

(iii) Production of 3-[4-({3-cWoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]propanoic acid

The title compound (595 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 202 (ϋ) using amixed solvent of ethyl 3-[4-({3-chloro-4-[3- (trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]propanoate (683 mg), IN aqueous sodium hydroxide solution (2 mL) and tetrahydrofuran (6 mL)/ethanol (6 mL). 1H-NMR (DMSOd₆) δ: 2.84 (2H, t, J= 6.4 Hz), 4.69 (2H, t, J= 6.4 Hz), 6.52 (IH, d, J= 3.0 Hz), 5 7.14 - 7.29 (2H, m), 7.32 (IH, d, J= 8.9 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.56-7.80 (3H, m), 7.94 (IH, s), 8.35 (IH, s), 9.10 (IH, s), 12.72 (IH, s).

(iv) Production of 3-[4-({3-cUoro-4-[3-(1rifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidm-5-yl]-N-[2-(memylsuhOnyl)ethyl]propanamide hydrochloride

3-[4-({3-CUoro-4-[3-(trifluoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3₅2- i o dJpyrinddm-S-yy-N-P-^emylsidfony^ethyypropanamide (140 mg) was obtained by the reaction in the same manner as in Synthesis Example 202 (in) using 3-[4-({3-chloro-4-[3- (trifluoromethyl)phenoxy]phenyl} amino)-5H-pyrrolo [3 ,2-d]pyrimidin-5-yl]propanoic acid (199 mg), 2-(methylsulfonyl)ethanamine (106 mg), 1-hydroxybenzotriazole monohydrate (84.7 mg), N- [3-(dimemylamino)propyl]-N'-ethylcarbodiimide hydrochloride (128.6 mg), triethylamine (0.1 mL) is and N,N-dimethylformamide (2 mL). The obtained 3-[4-({3-chloro-4-[3- (1rifluoromethyl)phenoxy]phenyl}atr^

(methylsulfonyl)ethyl]propanamide was dissolved in ethyl acetate (2 mL), 4N hydrochloric acid- ethyl acetate (0.1 mL) was added, and the precipitate was collected by filtration and dried to give the title compound (119 mg) as a white powder. 0 ¹H-NMR (DMSOd₆) δ: 2.82-2.90 (2H, m), 2.91 (3H, s), 3.18 (2H, t, J= 6.6 Hz), 3.40-3.51 (2H, m), 4.72-4.83 (2H, m), 6.70 (IH, d, J= 3.0 Hz), 7.23-7.32 (2H, m), 7.41 (IH, d, J= 8.8 Hz), 7.52 (IH, d, J= 7.7 Hz), 7.66 (IH, t, J= 7.7 Hz), 7.74 (IH, dd, J= 8.8 Hz, 2.5 Hz), 8.01-8.08 (2H, m), 8.67 (IH, t,

J= 5.6 Hz), 8.76 (IH, s), 10.80 (IH, s). Synthesis Example 236

Production of N-{2-[4-({3-cWoro-4-[3-(ttMuorome1hoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]etbyl} -3-hydroxypropanamide hydrochloride

5 N-{2-[4-({3-CMoro4-[3-(ttMuoromethoxy)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirrύdin-5-yl]ethyl}-3-hydroxypropananiide was obtained by the reaction in the same manner as in Synthesis Example 202 (iϋ) using 5-(2-aminoethyl)-N-{3-chloro-4-[3- (1rifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirddin-4-amine dihy^ mg), 3.6M aqueous solution (0.25 mL) of 3-hydroxypropanoic acid, 1-hydroxybenzotriazole i o monohydrate (231 mg), N-[3-(dimethylamino)propyl]-N-e1hylcarbodiimide hydrochloride (322 mg), triethylamine (0.8 mL) andN,N-drmethylformamide (3 mL). The obtained N-{2-[4-({3- cMoro-4-[3-(trifluoromethoxy)phenoxy]phenyl}a hydroxypropanamide was dissolved in ethyl acetate (2 mL), 4N hydrochloric acid-ethyl acetate (0.1 mL) was added, and the obtained product was crystallized from ethyl acetate to give the title

15 compound (80.9 mg) as white crystals.

¹H-NMR (DMSOd₆) δ: 2.21 (2H, t, J= 6.5 Hz), 3.39-3.51 (2H₅ m), 3.54 (2H, t, J= 6.5 Hz), 4.67 (2H, t, J= 7.0 Hz), 6.68 (IH, t, J= 3.0 Hz), 6.94-7.04 (2H, m), 7.16 (IH, d, J= 8.3 Hz), 7.36 (IH, d, J= 8.8 Hz), 7.54 (IH, t, J= 8.3 Hz), 7.72 (IH, dd, J= 8.8 Hz, 2.6 Hz), 7.93-8.04 (2H, m), 8.36 (IH, t, J= 5.8 Hz), 8.74 (IH, s), 10.23 (IH, s). Synthesis Example 237

Production of 5-[4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]pentane- 1 ,2-diol 5 (i) Production of 3-(2,2-dimethyl-l,3-dioxolan-4-yl)propan-l-ol

Pentane-l,2,5-triol (5.00 g) was dissolved in acetone (150 mL), 2,2-dimethoxypropane

(10.5 mL) and 4-methylbenzenesulfonic acid (794 mg) were added, and the mixture was stirred at room temperature for 1.5 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent, hexaneiethyl i o acetate=80:20 -> 50:50) to give the title compound (3.79 g) as a colorless oil.

¹H-NMR (CDCl₃) δ: 1.37 (3H, s), 1.42 (3H, s), 1.57-1.77 (4H, m), 2.05 (IH, br s), 3.53 (IH, t, J=

7.3 Hz)₅3.60-3.77 (2H, m), 4.004.21 (2H, m).

(ii) Production of 3-(2,2-dimethyl-l,3-dioxolan-4-yl)propyl methanesulfonate

The title compound (2.13 g) was obtained as a colorless oil by the reaction in the same 15 manner as in Synthesis Example 203 (ii) using 3-(2,2-dimethyl-l,3-dioxolan-4-yl)propan-l-ol (2.30 g), methanesulfonyl chloride (0.8 mL), triethylamine (3.0 mL) and ethyl acetate (50 mL).

¹H-NMR (CDCl₃) δ: 1.35 (3H, s), 1.41 (3H, s), 1.62 - 1.73 (2H, m), 1.75-2.02 (2H, m), 3.02 (3H, m), 3.50-3.57 (IH, m), 4.02-4.17 (2H, m), 4.21-4.36 (2H, m).

(iii) Production of 4-chloro-5-[3-(2,2-dimethyl-l ,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2- 0 d]pyrimidine The title compound (176 mg) was obtained as a white powder by the reaction in the same manner as in Synthesis Example 201 (ii) using 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (151 mg), 3- (2,2-dimethyl-l,3-dioxolan-4-yl)propyl methanesuLfonate (319 mg), cesium carbonate (574 mg) andN,N-dimethylformarnide (1.5 mL).

5 ¹H-NMR(CDCl₃) δ: 1.34 (3H, s), 1.40 (3H, s), 1.53-1.73 (2H, m), 1.80-2.13 (2H, m), 3.47-3.53 (IH, m), 3.97-4.18 (2H, m), 4.41-4.70 (2H, m), 6.72 (IH, d, J= 3.3 Hz), 7.51 (IH, d, J= 3.3 Hz), 8.70 (IH, s).

(iv) Production of 5-[4-({3-cWoro-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]pentane- 1 ,2-diol i o The crude product was obtained by the reaction in the same manner as in Synthesis

Example 201 (iii) using 4-chloro-5-[3-(2,2-dimethyl-l,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2- d]pyrimidine (171 mg), 3-cUoro-4-[3-(trifluoromethyl)phenoxy]aniline (195 mg) and isopropyl alcohol (3.5 mL). The crude product was dissolved in methanol (1 mL), IN hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3.5 hrs. The reaction mixture

15 was treated with IN aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 -» 95:5) to give the title compound (179 mg) as white crystals. 1H-NMR(DMSOd₆) δ: 1.03-1.41 (2H, m), 1.61-1.93 (2H, m), 3.08-3.28 (2H, m), 3.28-3.43 (IH, 0 m), 4.44 (IH, t, J= 5.5 Hz), 4.47-4.59 (3H, m), 6.49 (IH, d, J= 3.0 Hz), 7.17-7.27 (2H, m), 7.30 (IH, d, J= 9.1 Hz), 7.47 (IH, d, J= 8.5 Hz), 7.57-7.74 (3H, m), 7.97 (IH, d, J= 2.4 Hz), 8.34 (IH, s), 8.61 (IH, s).

Synthesis Example 238

Production of N-{2-[4-({3-cWoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrinddin-5-yl]ethyl}-3-hydroxypropanamide hydrochloride

N-{2-[4-({3-CUoro-4-[3-(tMuorome%l)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyririiidin-5-yl]ethyl}-3-hydroxypropanarnide was obtained by the reaction in the same manner as in Synthesis Example 202 (ϋi) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-

(trifluorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirnidin-4-amine dihydrochloride (300 mg),

3.6 M aqueous solution (0.25 mL) of 3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (231 mg), N-[3-(dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (330 mg), Methylamine (0.8 niL) andN,N-dimethyh^cbrmamide (3 mL). The obtained N-{2-[4-({3- cMoro-4-[3-(trffluoromethyl)phenoxy]phenyl}am hydroxypropanamide was dissolved in ethyl acetate (2 mL), and 4N hydrochloric acid-ethyl acetate

(0.1 mL) was added. The obtained product was recrystallized from ethyl acetate to give the title compound (63.1 mg) as a white powder. 1H-NMR (DMSOd₆) δ: 2.22 (2H,t, J= 6.5 Hz), 3.39-3.52 (2H, m), 3.55 (2H, t, J- 6.5 Hz), 4.65 (2H, t, J= 6.7 Hz), 6.67 (IH, d, J= 3.0 Hz), 7.24-7.32 (2H, m), 7.37 (IH, d, J= 8.8 Hz), 7.53 (IH, d, J= 8.0

Hz), 7.66 (IH, t, J= 8.0 Hz)₅7.72 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.96-8.01 (2H, m), 8.34 (IH, t, J= 5.8

Hz), 8.74 (IH, s), 10.17 (IH, s).

Synthesis Example 239

Production of N-{2-[4-({3-cMoro-4-[3-(Mfluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3_>2- d]pyrimidin-5-yl]ethyl}-3,3,3-trifluoropropanatnide

The title compound (64.0 mg) was obtained as yellow crystals by the reaction in the same manner as in Synthesis Example 202 (iϋ) using 5-(2-aminoethyl)-N-{3-cnloro-4-[3-

(tiMuoromethyl)phenoxy]phenyl}-5H-pyπ-olo[3_s2-d]pyrirniαln-4-amine dihydrochloride (150 mg), 3,3,3-trifluoropropanoic acid (0.06 mL), 1-hydroxybenzotriazole monohydrate (142 mg), N-[3- (dimethylamino)propyl]-N-ethylcarbodiimide hydrochloride (200 mg), triethylamine (0.4 mL) and N,N-dimethylformamide (1.5 mL) and crystallization from dϋsopropyl ether. 1H-NMR (DMSO-de) δ: 3.19 (2H,q, J= 11.2 Hz) 3.43 (2H, m), 4.58 (2H, t, J= 6.4 Hz), 6.52 (IH, d, J= 3.0 Hz), 7.18-7.26 (2H, m), 7.30 (IH, d, J= 9 Hz), 7.47 (IH, d, J= 7.5 Hz), 7.57-7.67 (2H, m), 7.76 (IH, dd, J= 9 Hz, 2.5 Hz), 8.00 (IH, d, J= 2.5 Hz), 8.36 (IH, s), 8.50 (IH, t, J= 5.3 Hz), 8.72 (IH, s).

Synthesis Example 240

Production of 3 - {2-[4-({3 -chloro-4-[3 -(trifluoromethyl)phenoxy]phenyl} amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethoxy}propane-l,2-diol hydrochloride

(i) Production of tert-butyl {2-[(2,2-dimeihyl-l,3-dioxolan-4-yl)methoxy]ethoxy}dirnethylsilane 60% Sodium hydride (890 mg) was suspended mN,N-dimethylformamide (60 mL), and 5 the suspension was cooled to 0°C. (2,2-Dimethyl-l ,3-dioxolan-4-yl)methanol (2.3 mL) was added dropwise and the mixture was stirred at O⁰C for 1 hr. To the reaction mixture was added (2- bromoethoxy)(tert-butyl)dimethylsilane (3 mL), and the mixture was stirred at O⁰C for 2 hrs. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over i o anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate^lOOiO -» 90:10) to give the title compound (1.04 g) as a yellow oil.

¹H-NMR (CDCl₃) δ: 0.06 (6H,s), 0.89 (9H,s), 1.36 (3H, s), 1.42 (3H, s), 3.47-3.63 (4H, m) 3.71- 3.79 (3H, m), 4.06 (IH, dd, J= 8.2 Hz, 6.3 Hz), 4.20-4.35 (IH, m).

15 (ϋ) Production of 2- [(2,2-dimethyl- 1 ,3-dioxolan-4-yl)methoxy]ethyl methanesutfonate tert-Butyl{2-[(2,2-α^ethyl-l,3-dioxolm4-yl)me1hoxy]ethoxy}dimethylsilane (1.03 g) was dissolved in tetrahydrofuran (20 mL), a 1.0 M solution (4 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was 0 extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), and subjected the reaction similar to that in Synthesis Example 203 (ϋ) using methanesulfonyl chloride (0.3 mL) and triethylamine (2 mL) to give the title compound (857 mg) as a yellow oil.

¹H-NMR (CDCl₃) δ: 1.36 (3H, s), 1.42 (3H, s), 3.07 (3H, s), 3.56 (IH, d, J= 1.4 Hz), 3.58 (IH, d, J= 1.9 Hz), 3.73 (IH, dd, J= 8.3 Hz, 6.3 Hz), 3.77-3.82 (2H, m), 4.06 (IH, dd, J= 8.3 Hz, 6.3 Hz), 4.24- 4.33 (IH, m), 4.35-4.41 (2H, m).

5 (iii) Production of 4-cUoro-5-{2-[(2,2-dime%l-l,3-dioxolan4-yl)me1hoxy]ethyl}-5H-pyrrolo[3,2- d]pyrimidine

The title compound (298 mg) was obtained as a colorless oil by the reaction in the same manner as in Synthesis Example 201 (ii) using 4-cHoro-5H-pyrrolo[3,2-d]pyrimidine (152 mg), 2- [(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy]ethyl methanesulfonate (327 mg), cesium carbonate i o (576 mg) and N,N-dimethylformamide (1.5 mL).

¹H-NMR (CDCl₃) δ: 1.33 (3H, s), 1.38 (3H, s), 3.37-3.50 (2H, m), 3.59 (IH, dd, J= 8.3 Hz, 6.6 Hz), 3.87 (2H, dt, J= 5.1 Hz, 2.2 Hz), 3.96 (IH, dd, J= 8.3 Hz, 6.6 Hz), 4.11-4.22 (IH, m), 4.66 - 4.72 (2H, m), 6.71 (IH, d, J= 3 Hz), 7.57 (IH, d, J= 3 Hz), 8.70 (IH, s). (iv) Production of 3-{2-[4-({3-cWoro4-[3-(trMuoromemyl)phenoxy]phenyl}arnino)-5H-

15 pyrrolo[3,2-d]pyrimidin-5-yl]ethoxy}propane-l,2-diol hydrochloride

3-{2-[4-({3-CUoro-4-[3-(trifluoromemyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethoxy} propane- 1 ,2-diol was obtained by the reaction in the same manner as in Synthesis Example 237 (iv) using 4-chloro-5-{2-[(2,2-dimethyl-l,3-dioxolan-4-yl)methoxy]ethyl}- 5H-pyrrolo[3,2-d]pyrimidine (295 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (359 mg) 0 and isopropyl alcohol (6 mL). The obtained 3-{2-[4-({3-chloro-4-[3-

(trifluoromethyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2-d]pyrirmdin-5-yl]etho diol was dissolved in ethyl acetate (6 mL), 4N hydrochloric acid-ethyl acetate (0.2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (360 mg) as a white powder.

¹H-NMR(DMSOd₆) δ: 3.10-3.26 (2H, m), 3.31-3.42 (IH, m), 3.42-3.56 (2H, m), 3.78-3.89 (2H, m), 4.774.89 (2H, m), 6.71 (IH, d, J= 3.0 Hz), 7.22-7.31 (2H, m), 7.36 (IH, d, J= 8.8 Hz), 7.52 (IH, d, J= 7.7 Hz), 7.60-7.73 (2H, m), 7.96-8.06 (2H, m), 8.75 (IH, s), 9.96 (IH, s). 5 Synthesis Example 241

Production of N- {2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl} amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethyl}-2-cyanoacetamide

The title compound (104 mg) was obtained as a yellow powder by the reaction in the same i o manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{3-chloro4-[3-

(trifluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrirrύdin4-amine dihydrochloride (201 mg), cyanoacetic acid (65.9 mg), 1-hydroxybenzotriazole monohydrate (215 mg), N-[3- (dime1hylarnino)propyl]-N-ethylcarbodiimide hydrochloride (300 mg), triethylamine (0.55 mL) and N,N-dimethylformamide (2.0 mL) and crystallization from dϋsopropyl ether. is ¹H-NMR PMSOd₆) δ: 3.36-3.47 (2H₅ m), 3.56 (2H, s), 4.58 (2H, t, J= 6.3 Hz), 6.52 (IH, d, J= 3.3 Hz), 7.18-7.28 (2H, m), 7.31 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.56-7.68 (2H, m), 7.73 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.99 (IH, d, J= 2.5 Hz), 8.36 (IH, s), 8.44 (IH, t, J= 5.8 Hz), 8.67 (IH, s). Synthesis Example 242

Production of N-{4-[4-({3-cMoro-4-[3-(trffluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3₅2- d]pyrimidin-5-yl]but-2-yn- 1 -yl} -2-(methylsulfonyl)acetamide (i) Production of tert-butyl (4-chlorobut-2-yn-l-yl)carbamate

5 4-Chlorobut-2-yn-l -amine hydrochloride (10.5 g) was dissolved in a mixed solvent of water (200 mL)/methanol (40 mL), di-tert-butyl dicarbonate (19 mL) was added, and the mixture was stirred at room temperature for 2 hrs. In this case, the reaction solution was maintained at pH 10-11 with 4N aqueous sodium hydroxide solution. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, i o dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=100:0 -> 80:20) to give the title compound (14.5 g) as a pale-yellow oil.

¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 3.89-4.06 (2H, m), 4.14 (2H, t, J= 2.1 Hz), 4.71 (IH, br s). (ii) Production of tert-butyl [4-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)but-2-yn-l-yl]carbamate is A mixture of 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (1.51 g), tert-butyl (4-chlorobut-2-yn- l-yl)carbamate (2.60 g), cesium carbonate (4.80 g) andN,N-dimethylformamide (15 mL) was stirred at room temperature for 2 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20 -> 33:67) to give the title compound (2.61 g) as an orange oil.

¹H-NMR (CDCl₃) δ: 1.44 (9H, s), 3.87-4.05 (2H, m), 4.71 (IH, s), 5.29 (2H, t, J= 2.1 Hz), 6.76 (IH, d, J= 3.3 Hz), 7.70 (IH, d, J= 3.3 Hz), 8.72 (IH, s).

5 (iii) Production of tert-butyl {4-[4-({3-cUoro4-[3-(1rifluoromethyl)phenoxy]phenyl}arnino)-5H- pyrrolo [3 ,2-d]pyrimidin-5-yl]but-2-yn- 1 -yl} carbamate

The title compound (1.86 g) was obtained as a colorless powder by the reaction in the same manner as in Synthesis Example 201 (iii) using tert-butyl [4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)but-2-yn-l-yl]carbamate (1.32 g), 3-cUoro^-[3-(trifluoromethyl)phenoxy]aniline (1.43 g) and o isopropyl alcohol (25 mL) and crystallization from hexane/dϋsopropyl ether.

¹H-NMR (CDCl₃) δ: 1.39 (9H, s), 4.03-4.08 (2H, m), 4.80 (IH, br s), 5.08 (2H, t, J= 2.1 Hz), 6.60 (IH, d, J= 3.3 Hz), 7.09 (IH, d, J= 8.8 Hz), 7.10-7.15 (IH, m), 7.18-7.23 (2H, m), 7.33 (IH, d, J= 7.8 Hz), 7.43 (IH, t, J= 7.8 Hz), 7.51 (IH, dd, J= 8.8 Hz, 2.5 Hz), 7.68 (IH, s), 7.97 (IH, d, J= 2.5 Hz), 8.56 (IH, s). 5 (iv) Production of 5-(4-aminobut-2-yn-l-yl)-N-{3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}- 5H-pyrrolo[3,2-d]pyrimidin4-amine dihydrochloride tert-Butyl {4-[4-({3-cUoro4-[3-(tiifluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]but-2-yn-l-yl} carbamate (1.90 g) was dissolved in tetrahydrofuran (35 mL), 2N hydrochloric acid (18 mL) was added, and the mixture was stirred at 6O⁰C for 16 hrs. To the o reaction mixture was added ethanol, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (802 mg) as a white powder. 1H-NMR (DMSOd₆) δ: 3.71-3.84 (2H, m), 5.97 (2H, s), 6.74 (IH, d, J= 3 Hz), 7.23-7.32 (2H, m),

7.36 (IH, d, J= 8.8 Hz), 7.52 (IH, d, J= 8.0 Hz), 7.66 (IH, t, J= 8.0 Hz), 7.76 (IH, dd, J= 8.8 Hz, 2.5 Hz), 8.05 (IH, d, J= 2.5 Hz), 8.21 (IH, d, J= 3 Hz), 8.42-8.60 (3H, m), 8.76 (IH₃ s), 10.49 (IH, s). (v) Production of N-{4-[4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]but-2-yn- 1 -yl} -2-(methylsulfonyl)acetarnide

The title compound (55.8 mg) was obtained as a pale-yellow powder by the reaction in the same manner as in Synthesis Example 202 (iii) using 5-(4-aminobut-2-yn-l-yl)-N-{3-chloro4-[3- (1rifluorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3₅2-d]pyrimidm4-amine dihydrochloride (204 mg), methanesulfonylacetic acid (102 mg), 1-hydroxybenzotriazole monohydrate (204 mg), N-[3- (dime1hylamino)propyl]-N-ethylcarbodiirriide hydrochloride (287 mg), triethylamine (0.5 mL) and N,N-dimethylformamide (2 mL) and crystallization from diisopropyl ether/ethyl acetate. 1H-NMR pMSO-de) δ: 3.07 (3H, s), 3.924.00 (2H, m), 4.02 (2H, s), 5.50 (2H, s), 6.55 (IH, d, J= 3 Hz), 7.18-7.28 (2H, m), 7.32 (IH, d, J= 9.1 Hz), 7.48 (IH, d, J= 7.1 Hz), 7.57-7.70 (2H, m), 7.76 (IH, d, J= 3 Hz), 8.02 (IH, d, J= 2.5 Hz), 8.39 (IH, s), 8.62 (IH, s), 8.77 (IH, t, J= 5.5 Hz). Synthesis Example 243

Production of N-{2-[4-({3-cWoro-4-[3-(tiifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidm-5-yl]ethyl}4,4,4-tiffluoro-3-hydroxy-3-memylbutariamide

The title compound (104 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{3-chloro4-[3- (1rMuorome1hyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyriinidin-4-amine dihydrochloride (201 mg), 4,4,4-trifluoro-3-hydroxy-3-methylbutanoic acid (131 mg), 1-hydroxybenzotriazolemonohydrate (159 mg), N-[3-(dimetihιylamino)propyl]-N-ethylcarbodiimide hydrochloride (372 mg), triefhylamine (0.55 mL) and tetrahydrofuran (2 mL) and crystallization from dϋsopropyl ether/ethyl

5 acetate.

¹H-NMR (DMSOd₆) δ: 1.36 (3H, s), 2.26-2.48 (2H, m), 3.36-3.56 (2H, m), 4.53 (2H, t, J= 6.7 Hz), 6.18 (IH, s), 6.51 (IH, d, J= 3.0 Hz), 7.15-7.26 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 8.0 Hz), 7.56-7.72 (2H, m), 7.81 (IH, dd, J= 8.8 Hz, 2.5 Hz), 8.04 (IH, d, J= 2.5 Hz), 8.35 (IH, s), 8.42 (IH, t, J= 5.9 Hz), 8.83 (IH, s). i o Synthesis Example 244

Production of 4-[4-({3-cMoro-4-[3-(triiluoromethyl)phenoxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]butanoic acid

(i) Production of ethyl 4-(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)butanoate

15 The title compound (1.70 g) was obtained as a yellow oil by the reaction in the same manner as in Synthesis Example 201 (ii) using 4-cMoro-5H-pyrrolo[3,2-d]pyrirnidine (1.01 g), ethyl 4-bromobutanoate (1.2 mL), cesium carbonate (3.23 g) andN,N-dimethylformamide (10 mL). 1H-NMR (CDCl₃) δ: 1.25 (3H, t, J= 7 Hz), 2.09-2.44 (4H, m), 4.13 (2H, q, J= 7 Hz), 4.56 (2H, t, J= 7.0 Hz), 6.73 (IH, d, J= 3 Hz), 7.50 (IH, d, J= 3 Hz), 8.71 (IH, s). 0 (ϋ) Production of ethyl 4-[4-({3-chloro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyritnidin-5-yl]butanoate

The title compound (2.69 g) was obtained as a yellow solid by the reaction in the same manner as in Synthesis Example 201 (iii) using ethyl 4-(4-cMoro-5H-pyrrolo[3,2-d]pyrirrudin-5- yl)butanoate (1.70 g), 3-chloro4-[3-(trifluoromethyl)phenoxy]aniline (2.19 g) and isopropyl alcohol 5 (35 mL).

¹H-NMR (CDCl₃) δ: 1.31 (3H, t, J= 7.2 Hz), 2.12-2.27 (2H₅ m), 2.50-2.61 (2H, m), 4.24 (2H, q, J= 7.2 Hz), 4.344.48 (2H, m), 6.60 (IH, d, J= 3.3 Hz), 7.08 (IH, d, J= 8.0 Hz), 7.11-7.17 (IH, m), 7.19-7.25 (2H, m), 7.32 (IH, d, J= 8.0 Hz), 7.43 (IH, t, J= 8.0 Hz), 7.82 (IH, dd, J= 8.8 Hz, 2.6 Hz), 8.00 (IH, d, J= 2.6 Hz), 8.16 (IH, s), 8.52 (IH, s). l o (iii) Production of 4-[4-({3-cUoro4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]butanoic acid

The title compound (2.02 g) was obtained as a white solid by the reaction in the same manner as in Synthesis Example 202 (ii) using ethyl 4-[4-({3-chloro4-[3- (1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrirrddin-5-yl]butanoate (2.69 g), IN

15 aqueous sodium hydroxide solution (7 mL) and a mixed solvent of tetrahydrofuran (20 mL)/ethanol (2O mL).

¹H-NMR (DMSOd₆) δ: 1.87-2.00 (2H, m), 2.20 (2H, t, J= 6.9 Hz), 4.52 (2H, t, J= 7.6 Hz), 6.50 (IH, d, J= 3.0 Hz), 7.17-7.28 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.57-7.76 (3H, m), 7.99 (IH, d, J= 2.5 Hz), 8.34 (IH, s), 8.61 (IH, s), 12.33 (IH, s). 0 Synthesis Example 245

Production of 4-[4-({3-cUoro-4-[3-(trifluorome1liyl)phenoxy]phenyl}amino)-5H-pyrrolo[3₅2- d]pyrimidin-5-yl]-N-[2-(me1hylsulfonyl)e1hyl]bu1miarnide

The title compound (142 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (ϋi) using 4-[4-({3-chloro-4-[3-

(trifluoromethyl)phenoxy]phenyl}anmo)-5H^ acid (250 mg),

2-(methylsulfonyl)ethanamine (128 mg), 1-hydroxybenzotriazole monohydrate (114 mg), N-[3- (dimethylamino)propyl]-N-ethylcarbodiirnide hydrochloride (492 mg), triethylamine (0.15 mL) and a mixed solvent of tetrahydrofuran (1.5

(1.5 mL) and crystallization from ethyl acetate.

¹H-NMR (DMSOd₆) δ: 1.90-2.03 (2H, m), 2.08-2.19 (2H, m), 2.97 (3H, s), 3.20-3.30 (2H₅ m), 3.40-3.52 (2H, m), 4.49 (2H, t, J= 7.2 Hz), 6.50 (IH, d, J= 3 Hz), 7.17-7.24 (IH, m), 7.24-7.27 (IH, m), 7.30 (IH, d, J= 9 Hz), 7.47 (IH, d, J= 8 Hz), 7.62 (IH, t, J= 8 Hz), 7.67 (IH, d, J= 3 Hz), 7.82 (IH, dd, J= 9 Hz, 2.5 Hz), 8.09 (IH, d, J= 2.5 Hz), 8.29 (IH, t, J= 5.6 Hz), 8.34 (IH, s), 8.79 (IH, s). Synthesis Example 246

Production of N-{2-[4-({3-cMoro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pvrimidin-5-yl]e1hyl}-3-hydroxypropara

N-{2-[4-({3-CWoro-4-[3-(trifluorome%l)phenoxy]phenyl}amino)-5H-ρyrrolo[3,2- 5 d]pyrirnidin-5-yl]ethyl} -3-hydroxypropanamide was obtained by the reaction in the same manner as in Synthesis Example 202 (iii) using 5-(2-aminoethyl)-N-{3-chloro-4-[3-

(tMuoromethyl)phenoxy]phenyl}-5H-pyiτolo[3,2-d]pyrirrddin4-arnine dihydrochloride (3.50 g), a 3.6 M aqueous solution (5.6 mL) of 3-hydroxypropanoic acid, 1-hydroxybenzotriazole monohydrate (4.56 g), N-[3-(dimethylamino)propyl]-N-ethylcarbodiirnide hydrochloride (10.1 g), i o triethylamine (10 mL) and a mixed solvent of tetrahydrofuran (17 mL)/N,N-dime1hylfoimamide (17 mL). The obtained N-{2-[4-({3-cWoro4-[3-(trmuorome%l)phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrinddin-5-yl]emyl}-3-hydroxypropanamide was dissolved in ethyl acetate (50 mL), methanesulfonic acid (0.155 mL) was added, and the mixture was stirred for 2 hrs. The reaction mixture was concentrated under reduced pressure and recrystallized from ethyl acetate to give the

15 title compound (1.04 g) as white crystals.

¹H-NMR (DMSOd₆) δ: 2.22 (2H, t, J= 6.3 Hz), 2.31 (3H, s), 3.41-3.51 (4H, m), 3.56 (2H, t, J= 6.5 Hz), 6.67 (IH, d, J= 3.0 Hz), 7.25-7.32 (2H, m), 7.37 (IH, d, J= 8.8 Hz), 7.50-7.56 (IH, m), 7.62- 7.74 (2H, m), 7.98 (IH, d, J= 2.8 Hz), 8.33 (IH, t, J= 5.5 Hz), 8.75 (IH, s), 10.11 (IH, s). Synthesis Example 247

Production of 4-[4-({3-cUoro4-[3-(trifluoromethyl)phenoxy]phenyl}airano)-5H-pyrrolo[3,2- d]pyrimidin-5-yl] -N-methoxybutanamide

The title compound (98.1 mg) was obtained as white crystals by the reaction in the same manner as in Synthesis Example 202 (iϋ) using 4-[4-({3-chloro-4-[3-

(1rifluoromethyl)phenoxy]phenyl}amino)-5H-pyiτolo[3,2-d]pyrimidin-5-yl]butanoic acid (252 mg), 0-methylhydroxylamine hydrochloride (85 mg), 1-hydroxybenzotriazole monohydrate (105 mg), N-[3-(dimethylamino)propyl]-N-ethylcarbodiirnide hydrochloride (484 mg), triethylamine (0.7 mL) and a mixed solvent of tetrahydrofuran (1 mL)/N,N-dimethylformamide (1 mL). 1H-NMR (DMSOd₆) δ: 1.92-1.99 (4H, m), 3.55 (3H, s), 4.46-4.56 (2H, m), 6.51 (IH, d, J= 2.8 Hz), 7.18-7.27 (2H, m), 7.30 (IH, d, J= 8.8 Hz), 7.47 (IH, d, J= 7.7 Hz), 7.58-7.69 (2H, m), 7.74-7.81 (IH, m), 8.03 (IH, s), 8.34 (IH, s), 8.75 (IH, br s), 11.02 (IH, br s). Synthesis Example 248

Production of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3- (1rifluorome&oxy)phenoxy]phenyl}aπ^

The title compound (203 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-methyl-4-[3- (triiluoromemoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine (238 mg), 3-hydroxy-3- methylbutanoic acid (0.0865 mL), 1 -ethyl-3-(3-dimethylaminopropyl)carbodiirnide hydrochloride (154 mg), 1-hydroxybenzotriazole monohydrate (109 mg), triethylamine (0.374 mL) andN,N- dimethylformamide (10.5 mL).

¹H-NMR (DMSO-d₆) δ 1.13 (6H, s), 2.12 (3H, s), 2.21 (2H, s), 3.41 (2H, m), 4.51 (2H, t, J= 6 Hz), 4.70 (IH, s), 6.47 (IH, d, J= 3 Hz), 6.88 (2H, m), 7.04 (2H, m), 7.47 (IH, t, J- 8 Hz), 7.61 (IH, d, J= 3 Hz), 7.65 (2H, m), 8.28 (2H, m), 8.73 (IH, br s). Synthesis Example 249

Production of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3- (trmhioromemyl)phenoxy]phenyl}aπmo)-5 (i) Production of 5-(2-aminoethyl)-N-{3-methyl-4-[3-(trifluoromethyl)phenoxy]phenyl}-5H- pyrrolo[3,2-d]pyrirnidin-4-amine dihydrochloride tert-Butyl {2-[4-({3-me%l-4-[3-(trifluorome%l)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl} carbamate (2.9 g) obtained in Synthesis Example 188 (i) was dissolved in tetrahydrofuran (80 mL)/2N hydrochloric acid (40 mL), and the mixture was stirred at 6O⁰C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (80 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (2.58 g) as a solid powder.

¹H-NMR (DMSOd₆) δ 2.20 (3H₅ s), 3.29 (2H, m), 5.06 (2H, m), 6.73 (IH, d, J= 3 Hz), 7.11 (IH, d, J- 9 Hz), 7.22 (2H, m), 7.48 (2H, m), 7.61 (2H, m), 8.08 (IH, d, J= 3 Hz), 8.42 (3H, br s), 8.70 (IH, s), 10.04 (IH, hr s). (ii) Production of 3-hydroxy-3-methyl-N-{2-[4-({3-methyl-4-[3- (1rifluorome1hyl)phenoxy]phenyl}arrm^

The title compound (203 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-methyl-4-[3- (trMuoromemyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin4-amine dihydrochloride (200 mg), 3-hydroxy-3-methylbutanoic acid (0.0644 mL), l-e1hyl-3-(3-dimethylammopropyl)carbodiirnide hydrochloride (115 mg), 1 -hydroxybenzotriazole monohydrate (81 mg), triethylamine (0.279 mL) andHN-dimethyrformamide (7.82 mL).

¹H-NMR (DMSOd₆) 8 1.13 (6H, s), 2.13 (3H, s), 2.21 (2H, s), 3.42 (2H, m), 4.52 (2H, t, J= 7 Hz), 4.69 (IH, s), 6.47 (IH, d, J= 3 Hz), 7.03 (IH, m), 7.18 (2H, m), 7.42 (IH, d, J= 8 Hz), 7.5-7.7 (4H, m), 8.26 (2H, m), 8.73 (IH, br s). Synthesis Example 250

Production of 2-{2-[4-({3-me1hyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}aniino)-5H-pyrrolo[3,2- d]pyrimidin.-5-yl]ethoxy}ethanol

The title compound (132 mg) was obtained colorless crystals by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-cHoro-5H-pyiτolo[3₅2-d]pyriniidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (139 mg) and 1- methyl-2-pyrrolidone (0.863 mL).

¹H-NMR (DMSO-de) 52.17 (3H₅ s)₅2.43 (3H, s), 3.51 (4H₅ brs), 3.84 (2H₅1, J= 4.5 Hz), 4.63 (2H, t, J= 4.5 Hz), 4.73 (IH, t, J= 4.5 Hz)₅ 6.49 (IH, d, J= 3 Hz), 6.93 (IH, d, J= 8 Hz), 7.16 (IH₅ dd, J= 9 Hz, 3 Hz), 7.23 (IH₅ d, J= 8 Hz), 7.56 (2H₅ m), 7.65 (IH, d, J= 3 Hz), 8.17 (IH, d₅ J= 3 Hz)₅ 8.28 (lH, s), 8.78 (IH, br s). Synthesis Example 251

Production of N-{2-[4-({3-methyl-4-[(6-me1hylpyridm-3-yl)oxy]phenyl}arnino)-5H-pyrrolo[3₅2- d]pyrimidm-5-yl]ethyl}-2-(methylsulfonyl)acetamide (i) Production of tert-butyl {2-[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]efhyl}carbamate

The Me compound (799 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-cUoro-5H-pyirolo[3,2-d]pyrirnidin-5- yl)ethyl]carbamate (500 mg), 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (542 mg) and isopropyl alcohol (5 mL).

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 2.24 (3H, s), 2.52 (3H, s), 3.49 (2H, m), 4.46 (2H, m), 5.18 (IH, m), 6.58 (IH, d, J= 3 Hz), 6.89 (IH, d, J- 9 Hz), 7.0-7.2 (3H, m), 7.65 (2H, m), 8.27 (IH, d, J= 2

Hz), 8.41 (IH, br s), 8.48 (IH, s). (ii) Production of 5-(2-aminoethyl)-N-{3-metiiyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyπolo[3,2-d]pyrimidin-4-amine trihydrochloride tert-Butyl {2-[4-({3-methyl-4-[(6-me1h.ylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}carbamate (790 mg) was dissolved in tetrahydrofiiran (24 mL)/2N hydrochloric acid (12 mL), and the mixture was stirred at 6O⁰C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (30 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (701 mg) as a solid powder.

¹H-NMR (DMSO-d_δ) 62.23 (3H, s), 2.68 (3H, s), 3.29 (2H, m), 5.11 (2H, m), 6.74 (IH, d, J= 3 Hz), 7.16 (IH, d, J= 8 Hz), 7.52 (IH, d, J= 9 Hz), 7.62 (IH, s), 7.80 (IH, m), 7.96 (IH, m), 8.10 (IH, m),

8.37 (IH, d, J= 3 Hz), 8.51 (3H, br s), 8.71 (IH, s).

(iii) Production of N-{2-[4-({3-methyl-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrmτidm-5-yl]ethyl}-2-(memylsulfonyl)acetamide The title compound (205 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-methyl-4-[(6- methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrirmdin4-amine trihydrochloride (250 mg), 2-(methylsulfonyl)acetic acid (107 mg), l-ethyl-3-(3-dimethylaminopropyl)carbodiimide 5 hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) andN,N-dimemylformamide (10 mL).

¹H-NMR (DMSOd₆) δ 2.17 (3H, s), 2.44 (3H, s), 3.34 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.05 (2H₃ s), 4.55 (2H, t, J= 6 Hz), 6.47 (IH₅ d, J= 3 Hz), 6.94 (IH, d, J= 9 Hz), 7.1-7.3 (2H, m), 7.55 (3H, m), 8.18 (IH, d, J= 3 Hz), 8.28 (IH, s), 8.51 (IH, br s), 8.67 (IH, t, J= 5 Hz). i o Synthesis Example 252

Production of 2-[2-(4-{[3-cMoro-4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethoxy]ethanol

The title compound (149 mg) was obtained as colorless crystals by the method in the same 5 manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-cMoro^-(pyridin-2-ylmethoxy)aniline (152 mg) and 1- methyl-2-ρyrrolidone (0.863 mL).

¹H-NMR (DMSOd₆) δ 3.47 (4H, m), 3.81 (2H, t, J= 4.5 Hz), 4.61 (2H₅1, J= 4.5 Hz), 4.70 (IH, t, J= 4.5 Hz)₅ 5.27 (2H, s), 6.48 (IH, d, J= 3 Hz), 7.20 (IH₅ d, J= 9 Hz)₅ 7.37 (IH₅ dd, J= 7 Hz₅4.5 Hz), 7.49 (IH, dd, J= 9 Hz, 3 Hz), 7.58 (IH, d, J= 8 Hz), 7.64 (IH, d, J= 3 Hz), 7.84 (IH, d, J= 3 Hz), 7.88 (IH, m), 8.27 (IH, s), 8.59 (IH, dd, J= 3 Hz, 1 Hz), 8.70 (IH, br s).

Synthesis Example 253

Production of N-[2-(4-{[3-cMoro-4-φyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetaniide

(i) Production of tert-butyl [2-(4-{[3-cMoro4-(pyriαin-2-ylmethoxy)phenyl]arnino}-5H- pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate

The title compound (812 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-cWoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethyl]carbamate (500 mg), 3-cUoro-4-(pyridin-2-ylmethoxy)anπine (594 mg) and isopropyl alcohol (5 mL).

¹H-NMR (CDCl₃) δ 1.48 (9H, s), 3.46 (2H, m), 4.43 (2H, m), 5.19 (IH, t, J= 5 Hz), 5.29 (2H, s),

6.56 (IH, d, J= 3 Hz), 6.98 (IH, d, J= 9 Hz), 7.14 (IH, d, J= 3 Hz)₅7.2-7.3 (2H, m), 7.6-7.8 (3H, m), 7.87 (IH, d, J= 3 Hz), 8.46 (IH, s), 8.51 (IH, br s), 8.59 (IH, m).

(ii) Production of 5-(2-aminoe1hyl)-N-[3-cUoro-4-(pyridin-2-ylmethoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine trihydrochloride tert-Butyl [2-(4-{[3-cWoro4-(pyridin-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]carbamate (790 mg) was dissolved in tetrahydrofuran (24 mL)/2N hydrochloric acid (12 mL), and the mixture was stirred at 6O⁰C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (30 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (826 mg) as 5 a solid powder.

¹H-NMR (DMSO-dβ) δ 3.29 (2H, m), 5.07 (2H, m), 5.49 (2H, s), 6.73 (IH, dd, J= 3 Hz, 1 Hz), 7.34 (IH, d, J= 9 Hz), 7.52 (IH, dd, J= 9 Hz, 3 Hz), 7.68 (IH, m), 7.74 (IH, d, J= 2 Hz), 7.85 (IH, m), 8.09 (IH, d, J= 3 Hz), 8.24 (IH, m), 8.47 (3H, br s), 8.69 (IH, s), 8.77 (IH, m), 10.19 (IH, br s). (iii) Production of N-[2-(4-{[3-cWoro-4-(pyridm-2-ylmethoxy)phenyl]amino}-5H-pyrrolo[3,2- i o d]pyrirm^'dm-5-yl)emyl]-2-(methylsulfonyl)acetamide

The title compound (182 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-[3-chloro4-(pyridin- 2-ylmethoxy)phenyl]-5H-pyπ-olo[3,2-d]pyrimidm4-ammetrihydrochloride (261 mg), 2- (methylsulfonyl)acetic acid (107 mg), l-emyl-3-(3-dime1hylaminopropyl)carbodiimide is hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) andN,N-dimethylformamide (10 mL).

¹H-NMR (DMSOd₆) δ 3.10 (3H, s), 3.44 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.53 (2H, t, J= 6 Hz), 5.28 (2H, s), 6.46 (IH, d, J= 3 Hz), 7.22 (IH, d, J= 9 Hz), 7.37 (IH, dd, J= 8 Hz, 6 Hz), 7.57 (3H, m), 7.78 (IH, d, J= 2 Hz), 7.89 (IH, dt, J= 2 Hz, 8 Hz), 8.26 (IH, s), 8.49 (IH, br s), 8.60 (IH, d, J= 5 0 Hz), 8.67 (IH, t, J= 6 Hz). Synthesis Example 254 OH

Production of tert-butyl (2S,4R)-4-hydroxy-2-[({2-[4-({3-methyl-4-[3- (1rMuorome1hyl)phenoxy]phenyl}amino)-5H-pyiτolo[3,2-d]pyilmidin-5- yl]ethyl}amino)carbonyl]pyrrolidine-l-carboxylate

5 The title compound (310 mg) was obtained as a colorless powder by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-methyl-4-[3- (triiluoromethyl)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (300 mg), (4R)-l-(tert-butoxycarbonyl)-4-hydroxy-L-proline (118 mg), l-ethyl-3-(3- climethylarninopropyl)carbodiirnide hydrochloride (172 mg), 1-hydroxybenzotriazole monohydrate io (122 mg),triethylamine (0.418 mL) andN,N-dimethylformamide (11.73 mL).

¹H-NMR (CDCl₃) δ 1.43 (9H, s), 1.9-2.1 (2H, m), 2.22 (3H, s), 2.50 (IH, br s), 3.44 (2H, m), 3.61 (2H, m), 4.44 (4H, m), 6.58 (IH, d, J= 3 Hz), 6.94 (IH, d, J= 9 Hz), 7.10 (IH, m), 7.18 (2H, m), 7.27 (2H, m), 7.39 (IH, d, J= 8 Hz)₅ 7.65 (IH, d, J= 9 Hz), 7.73 (IH, m), 8.39 (IH, br s), 8.48 (IH, s). i 5 Synthesis Example 255 OH

Production of (4R)-4-hydroxy-N-{2-[4-({3-me1hyl-4-[3-(1rifluoromethyl)phenoxy]phenyl}amino)- 5H-pyrolo[3,2-d]pyrimdm-5-yl]et^ tert-Butyl (2S,4R)4-hydroxy-2-[({2-[4-({3-methyl-4-[3- 5 (trifluoromethyl)phenoxy]ρhenyl } amino)-5H-pyrrolo [3 ,2-d]pyrimidin-5- yl]ethyl}amino)carbonyl]pyrrolidlne-l-carboxylate (230 mg) was dissolved in dichloromethane (2.39 mL), trifluoroacetic acid (1.79 mL) was added, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate/tetrahydrofuran (1 : 1, 50 mL). The organic layer was washed i o with saturated aqueous sodium hydrogen carbonate (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to basic silica gel chromatography (ethyl acetate/methanol=400/0 -> 80/20). The fractions containing the title compound were collected and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, 4N hydrochloric acid (0.252 mL) was added, and the mixture was crystallized to give the title is compound (136 mg).

¹H-NMR (DMSO-d₆) δ 1.66 (lH, m), 2.14 (1H, m), 2.21 (3H, s), 3.04 (IH, m), 3.23 (lH, m), 3.49 (3H, m), 3.67 (IH, m), 4.16 (2H, m), 4.36 (IH, m), 4.83 (2H, m), 5.55 (IH, br s), 6.66 (IH, d, J= 3 Hz), 7.13 (IH, d, J= 9 Hz), 7.23 (2H, m), 7.49 (2H, m), 7.61 (2H, m), 7.94 (IH, m), 8.56 (IH, m), 8.68 (IH, s), 8.95 (IH, m), 10.02 (2H, m). Synthesis Example 256

Production of 2-(mefhylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (tiMuorome1hyl)phenoxy]phenyl}am^ 5 methanesulfonate

2-(Methylsulfonyl)-N-{2-[4-({3-methyl-4-[3-(tM^

5H-pyrrolo[3,2-d]pyriniidin-5-yl]ethyl}acetamide (680 mg) was dissolved in ethyl acetate (3.4 mL), methanesulfonic acid (0.0887 mL) was added at 50⁰C, and the mixture was stirred for 10 min. and further stirred at room temperature for 2 hrs. The precipitated crystals were collected by filtration i o and washed with diisopropyl ether to give the title compound (797 mg) as colorless crystals.

¹H-NMR (DMSOd₆) δ 2.20 (3H, s), 2.31 (3H, s), 3.05 (3H₅ s), 3.55 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.68 (2H, t, J= 6 Hz), 6.65 (IH, d, J= 3 Hz), 7.13 (IH, d, J= 9 Hz), 7.23 (2H, m)_s 7.49 (2H, m), 7.62 (2H, m), 7.91 (IH, d, J= 3 Hz), 8.70 (2H₅ m), 9.84 (IH, br s). Synthesis Example 257

Production of 2-{2-[4-({3-cUoro-4-[(6-methylpyriα4n-3-yl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethoxy}ethanol The title compound (133 mg) was obtained as colorless crystals by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-cUoro-5H-pyrrolo[3,2-d]pyrirnidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-cUoro-4-[(6-methylpyridin-3-yl)oxy]aniline (152 mg) and 1- methyl-2-pyrrolidone (0.863 mL). 1H-NMR (DMSO-de) δ 2.44 (3H, s), 3.48 (4H, m), 3.83 (2H, t, J= 4.5 Hz)₅4.64 (2H, t, J= 4.5 Hz)₃ 4.71 (IH, t, J= 4.5 Hz), 6.52 (IH, d, J= 3 Hz), 7.18 (IH, d, J= 9 Hz), 7.24 (2H, m), 7.62 (IH₅ dd, J= 9 Hz, 2 Hz), 7.69 (IH, d, J= 3 Hz), 8.00 (IH₅ d, J= 2 Hz), 8.20 (IH, d, J= 1 Hz), 8.34 (IH, s), 8.96 (lH, br s).

Synthesis Example 258

Production of N-{2-[4-({3-cUoro-4-[(6-methylpyridm-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-(methylsurfonyl)acetarnide

(i) Production of tert-butyl {2-[4-({3-cMoro-4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate The title compound (673 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethyl]carbamate (500 mg), 3-cUoro4-[(6-methylpyridin-3-yl)oxy]anirine (594 mg) and isopropyl alcohol (5 mL). 1H-NMR (CDCl₃) δ 1.49 (9H, s), 2.53 (3H₅ s), 3.48 (2H, m), 4.46 (2H₅ m)₅ 5.26 (IH₅1, J= 6 Hz), 6.59 (IH, d, J= 3 Hz), 7.01 (IH, d, J= 9 Hz), 7.09 (IH, d, J= 8 Hz), 7.18 (2H, m), 7.85 (IH₅ dd, J= 9 Hz, 3 Hz), 8.00 (IH, d, J= 3 Hz), 8.30 (IH, d, J= 3 Hz), 8.50 (IH, s), 8.63 (IH, br s).

(ii) Production of 5-(2-aminoethyl)-N-{3-cMoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-5H- pyrrolo[3,2-d]pyrimidin-4-arnine trihydrochloride tert-Butyl {2-[4-({3-cUoro4-[(6-me1hylpyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyritnidin-5-yl]ethyl}carbamate (643 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric acid (9.75 mL), and the mixture was stirred at 60°C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (50 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (646 mg) as a solid powder.

¹H-NMR (DMSOd₆) δ 2.68 (3H, d, J= 6 Hz), 3.30 (2H, m), 5.14 (2H, m), 6.77 (IH, d, J= 3 Hz),

7.40 (IH, m), 7.6-7.9 (2H, m), 8.00 (2H, m), 8.12 (IH, m), 8.52 (4H, m), 8.77 (IH, s), 10.50 (IH, m).

(ϋi) Production of N-{2-[4-({3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo [3 ,2-d]pyrirnidin-5-yl]ethyl} -2-(methylsulfonyl)acetamide

The title compound (230 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[(6- methylpyridin-3-yl)oxy]phenyl}-5H-pyrrolo[3,2-d]pyrirnidin-4-amine trihydrochloride (261 mg), 2-(methylsulfonyl)acetic acid (107 mg), l-ethyl-3-(3-dime1hylaminopropyl)carbodiirnide hydrochloride (149 mg), 1 -hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) and N,N-dimethylformamide (10 mL). 1H-NMR (DMSOd₆) δ 2.45 (3H, s), 3.10 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.04 (2H, s), 4.56 (2H, t,

J= 6 Hz), 6.50 (IH, d, J= 3 Hz), 7.18 (IH, d, J= 9 Hz), 7.25 (IH, d, J= 2 Hz), 7.62 (IH, d, J= 3 Hz), 7.70 (IH, dd, J= 9 Hz, 3 Hz), 7.95 (IH, d, J= 2 Hz), 8.22 (IH, m), 8.34 (IH, s), 8.67 (2H, m).

Synthesis Example 259

Production of 2-{2-[4-({3-cWoro-4-[(5-cUoropyridin-3-yl)oxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyriinidin-5-yl]ethoxy}efhanol

The title compound (145 mg) was obtained as colorless crystals by the method in the same manner as in Synthesis Example 183 using 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (150 mg), 3-cWoro-4-[(5-cMoropyridin-3-yl)oxy]aniline (165 mg) and 1- methyl-2-pyrrolidone (0.863 niL). 1H-NMR (DMSO-dβ) δ 3.49 (4H, m), 3.84 (2H, t, J= 4.5 Hz), 4.65 (2H, t, J= 4.5 Hz), 4.72 (IH, t, J= 4.5 Hz), 6.53 (IH, d, J= 3 Hz), 7.33 (IH, d, J= 9 Hz), 7.49 (IH, m), 7.69 (2H, m), 8.04 (IH, d, J= 2 Hz), 8.32 (IH, d, J= 2 Hz), 8.36 (IH, s), 8.40 (IH, d, J= 2 Hz), 9.02 (IH, br s). Synthesis Example 260

Production of N-{2-[4-({3-cMoro-4-[(5-cUoropyriά4n-3-yl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-(methylsuh^cbnyl)acetamide (i) Production of tert-butyl {2-[4-({3-cMoro-4-[(5-chloropyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3₅2-d]pyriωidin-5-yl]ethyl}carbamate

The title compound (769 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 188 (i) using tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5- yl)ethyl]carbamate (500 mg), 3-cUoro-4-[(5-cWoropyridin-3-yl)oxy]aniline (643 mg) and isopropyl alcohol (5 mL).

¹H-NMR (CDCl₃) δ 1.50 (9H, s), 3.49 (2H, m), 4.48 (2H, m), 5.21 (IH, t, J= 6 Hz), 6.60 (IH, d, J=

3 Hz), 7.11 (IH, d, J= 9 Hz), 7.21 (2H, m), 7.94 (IH, dd, J= 9 Hz, 3 Hz), 8.06 (IH, d, J= 3 Hz), 8.29

(2H, m), 8.53 (IH, s), 8.69 (IH, br s). (ϋ) Production of 5-(2-arninoethyl)-N-{3-chloro-4-[(5-chloropyridin-3-yl)oxy]phenyl}-5H- pvrrolo[3,2-d]pyrirrridm-4-amine trihydrochloride tert-Butyl {2-[4-({3-cMoro-4-[(5-cUoropyriα^-3-yl)oxy]phenyl}arnino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl} carbamate (700 mg) was dissolved in tetrahydrofuran (19.5 mL)/2N hydrochloric acid (9.75 mL), and the mixture was stirred at 60°C for 16 hrs. The reaction mixture was concentrated under reduced pressure, ethanol (50 mL) was added to the residue and the mixture was concentrated again under reduced pressure. Ethyl acetate was added to the residue and the solid was collected by filtration and dried under reduced pressure to give the title compound (663 mg) as a solid powder.

¹H-NMR (DMSOd₆) δ 3.30 (2H, m), 5.09 (2H, m), 6.77 (IH, d, J= 3 Hz), 7.40 (IH, d, J= 9 Hz), 7.61 (IH, m), 7.69 (IH, dd, J= 9 Hz, 2 Hz), 7.96 (IH, d, J= 2 Hz), 8.12 (IH, d, J= 3 Hz), 8.35 (IH, d,

J= 2 Hz), 8.40 (3H, s), 8.46 (IH, d, J= 2 Hz), 8.77 (IH, s), 10.36 (IH, m).

(iii) Production of N-{2-[4-({3-cUoro-4-[(5-cWoropyridin-3-yl)oxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrmτiα!m-5-yl]emyl}-2-(me&ylsulfonyl)acetamide The title compound (255 mg) was obtained as colorless powder crystals by the reaction in the same manner as in Synthesis Example 155 (iv) using 5-(2-aminoethyl)-N-{3-chloro-4-[(5- ctøoropyridin-3-yl)oxy]phenyl}-5H-pym)lo[3,2-d]pyr^ (271 mg), 2-

(methylsulfonyl)acetic acid (107 mg), l-ethyl-3-(3-dimethylarninopropyl)carbodiimide hydrochloride (149 mg), 1-hydroxybenzotriazole monohydrate (105 mg), triethylamine (0.360 mL) andN,N-dimethylformamide (10 mL).

¹H-NMR (DMSOd₆) δ 3.09 (3H, s), 3.45 (2H, m), 4.04 (2H, s), 4.56 (2H, t, J= 6 Hz)₅6.50 (IH, d, J= 3 Hz), 7.34 (IH, d, J= 9 Hz), 7.50 (IH, m), 7.63 (IH, d, J= 3 Hz), 7.76 (IH, dd, J= 9 Hz, 2 Hz), 7.99 (IH, d, J= 3 Hz), 8.32 (IH, d, J= 2 Hz), 8.35 (IH, s), 8.40 (IH, d, J= 2 Hz), 8.66 (IH, m), 8.73 (lli br s).

Synthesis Example 261

Production of tert-bu1yl 4-[2-cWoro-4-({5-[2-(2-hydroxyemoxy)ethyl]-5H-pyrrolo[3,2-d]pyrirnidin- 4-yl}amino)phenoxy]piperidine-l-carboxylate (i) Production of tert-butyl 4-{4-[(5-{2-[2-(benzoyloxy)e1hoxy]emyl}-5H-pyrrolo[3,2-d]pyrirniditi- 4-yl)amino]-2-chlorophenoxy}piperidine-l-carboxylate

A mixture of 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (3.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)piperidine-l-carboxylate (3.27 g) and isopropyl alcohol (50 mL) was stirred at 80⁰C overnight. The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 — » 10:90). The object fraction was concentrated under reduced pressure. The 5 residue was crystallized from ethyl acetate-dϋsopropyl ether to give the title compound (4.70 g) as a white powder.

¹H-NMR (CDCl₃) δ 1.48 (9H, s), 1.71-1.92 (4H₅ m), 3.33-3.45 (2H, m), 3.62-3.73 (2H, m), 3.90- 3.97 (2H, m), 4.05 (2H, t, J= 4.4 Hz), 4.29-4.39 (IH, m), 4.464.52 (2H, m), 4.56 (2H, t, J= 4.4 Hz), 6.61 (IH, d, J= 3.3 Hz), 6.72 (IH, d, J= 8.7 Hz), 7.19 (IH, d, J= 3.3 Hz), 7.29 (IH, dd, J= 8.7, 2.7 i o Hz), 7.33-7.40 (2H, m), 7.50-7.57 (IH, m), 7.69 (IH, d, J= 2.7 Hz), 7.78-7.83 (2H, m), 8.47 (IH, s), 8.55 (lH, br s).

(ii) Production of tert-butyl 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-yl} amino)phenoxy]piperidine- 1 -carboxylate tert-Butyl 4-{4-[(5-{2-[2-(penzoyloxy)emoxy^ is yl)amino]-2-chlorophenoxy}piperidine-l -carboxylate (636 mg) was dissolved in amixed solvent of methanol (10 mL) and tetrahydrofuran (10 mL), IN aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was 0 evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 -»10:90). The object fraction was concentrated under reduced pressure. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethyl acetate-diethyl ether to give the title compound (498 mg) as a white powder.

¹H-NMR (CDCl₃) δ 1.47 (9H, s), 1.75-1.96 (4H, m), 2.27 (IH, br s), 3.33-3.45 (2H, m), 3.63-3.82 (6H, m), 4.00 (2H, t, J= 4.5 Hz)₅4.39-4.47 (IH, m), 4.54 (2H, t, J= 4.5 Hz), 6.58 (IH, d, J= 3.3 Hz), 6.95 (IH, d, J= 8.8 Hz), 7.17 (IH, d, J= 3.3 Hz), 7.52 (IH, dd, J= 8.8, 2.7 Hz), 7.70 (IH, d, J= 2.7 Hz), 8.46 (IH, s), 8.60 (IH, br s). Synthesis Example 262

Production of 4-[2-cMoro-4-({5-[2-(2-hydroxye1hoxy)e1hyl]-5H-pyrrolo[3,2-d]pyrirnidin-4- yl} arnino)phenoxy]-N-(2,6-difluorophenyl)piperidine-l -carboxamide hydrochloride (i) Production of 2-[2-(4-{[3-cUoro-4-(piperidin-4-yloxy)phenyl]arnino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride

4N Hydrochloric acid/ethyl acetate solution (20 mL) and ethanol (10 mL) were added to tert-butyl 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]e^ chlorophenoxy}piperidine-l-carboxylate (3.82 g), and the mixture was stirred at room temperature for 5 hrs. The reaction mixture was concentrated under reduced pressure, and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (3.68 g) as a white powder. ¹H-NMR (DMSOd₆) δ 1.85-2.00 (2H, m), 2.07-2.21 (2H, m), 3.02-3.28 (4H, m), 3.77 (2H, m), 3.88 (2H, m), 4.29 (2H, m), 4.70-4.79 (IH, m), 4.89 (2H, m), 6.60 (IH, d, J= 3.0 Hz), 7.25 (IH, d, J= 8.7 Hz), 7.42-7.51 (3H, m), 7.61-7.73 (4H, m), 7.98 (IH, d, J= 3.0 Hz), 8.57 (IH, s), 9.20-9.50 (2H, m), 9.85 (lH, br s). © Production of 4-[2-cMoro^-({5-[2-(2-hydroxye1hoxy)e1hyl]-5H-pyrrolo[3,2-d]pyriniidin-4- yl} amino)phenoxy]-N-(2,6-difluorophenyl)piperidine-l -carboxamide hydrochloride

To a mixture of 2-[2-(4-{[3-cHoro-4-(piperidin-4-yloxy)phenyl]arnino}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate 5 solution (10 mL), ethyl acetate (15 mL) and tetrahydrofuran (5 mL) was added 2,6-difluorophenyl isocyanate (93 mg) with vigorous stirring. The mixture was stirred at room temperature for 2 hrs, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (8 mL) and i o tetrahydrofuran (2 mL). IN Aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent,

15 methanol:ethyl acetate=0: 100 -> 15:85). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and IN hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (202 mg) as a white powder. 0 ¹H-NMR (DMSOd₆) δ 1.60-1.75 (2H, m), 1.91-2.04 (2H, m), 3.20-3.55 (6H, m), 3.68-3.81 (2H, m), 3.84 (2H, m), 4.724.85 (3H, m), 6.67 (IH, d, J= 3.0 Hz), 7.06-7.17 (2H, m), 7.23-7.32 (IH, m), 7.35 (IH, d, J= 8.9 Hz), 7.51 (IH, dd, J= 8.9, 2.5 Hz), 7.77 (IH, d, J= 2.5 Hz), 7.99 (IH, d, J- 3.0

Hz), 8.34 (IH₃ s), 8.68 (IH, s), 9.79 (IH, br s).

Production of 2-(2-{4-[(3-cWoro-4-{[l-(cyclopentylcarbonyl)piperidm-4-yl]oxy}phenyl)amino]- 5H-pyπ"olo[3,2-d]pyrirnidin-5-yl}efhoxy)ethanol hydrochloride The title compound (207 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 262 (ii) using 2-[2-(4-{[3-chloro-4-(piperidin-4- yloxy)phenyl]arrmo}-5H-pyrrolo[3_>2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and cyclopentanecarbonyl chloride (80 mg). 1H-NMR (DMSOd₆) δ 1.45-2.06 (12H, m), 2.95-3.08 (IH, m), 3.30-3.55 (6H, m), 3.69-3.80 (2H, m), 3.83 (2H, t, J= 4.4 Hz), 4.70-4.85 (3H, m), 6.67 (IH, d, J= 3.0 Hz), 7.34 (IH, d, J= 9.0 Hz), 7.50 (IH, dd, J= 9.0, 2.7 Hz), 7.76 (IH, d, J= 2.7 Hz), 7.99 (IH, d, J= 3.0 Hz), 8.68 (IH, s), 9.82 (IH, br s). Synthesis Example 264

Production of 4-[2-cUoro-4-({5-[2-(2-hydroxye1hoxy)e%l]-5H-pyrrolo[3,2-d]pyrimidin-4- yl}amino)phenoxy]-N-cyclopentylpiperidine-l-carboxamide hydrochloride To a solution of 1,1 '-carbonylbis(lH-imidazole) (162 mg) in tetrahydrofuran (5 mL) was added a solution of cyclopentylamine (85 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1 hr. A solution of 2-[2-(4-{[3-chloro-4-(piperidin-4- yloxy)phenyl]amko}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 5 mg) and triethylamine (0.153 mL) in tetrahydrofuran (1 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was dissolved in methanol (8 mL) and tetrahydrofuran (2 mL). IN Aqueous i o sodium hydroxide solution (1 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100 — > is 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and IN hydrochloric acid/ethyl acetate solution (0.5 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (188 mg) as a white powder. 1H-NMR (DMSO-de) δ 1.30-1.95 (12H, m), 3.15-3.27 (2H, m), 3.40-3.50 (4H, m), 3.55-3.67 (2H, 0 m), 3.83 (2H, t, J= 4.6 Hz), 3.82-3.98 (IH, m), 4.62-4.72 (IH, m), 4.80 (2H, m), 6.30 (IH, d, J= 6.4 Hz), 6.67 (IH, d, J= 3.0 Hz), 7.32 (IH, d, J= 9.0 Hz), 7.50 (IH, dd, J= 9.0, 2.6 Hz), 7.75 (IH, d, J= 2.6 Hz), 7.99 (IH, d, J= 3.0 Hz), 8.68 (IH, s), 9.82 (IH, br s).

Synthesis Example 265

Production of 4-[2-cMoro4-({5-[2-(2-hydroxyetiioxy)e1hyl]-5H-pyrrolo[3,2-d]pyrijmc3Jn-4- yl}amino)phenoxy]-N-(4-me1hoxyplienyl)piperidine-l-carboxamide hydrochloride

The title compound (209 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 262 (ii) using 2-[2-(4-{ [3-chloro-4-(piperidin-4- yloxy)phenyl]ammo}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and 4-methoxyphenyl isocyanate (75 mg).

¹H-NMR (DMSO-dβ) δ 1.60-1.75 (2H₅ m), 1.90-2.03 (2H, m), 3.34-3.51 (6H₅ m), 3.68-3.80 (2H₅ m), 3.70 (3H, s), 3.84 (2H, t, J= 4.5 Hz)₅4.70-4.85 (3H, m), 6.68 (IH₅ d, J= 3.2 Hz)₅ 6.82 (2H₅ d, J=

9.1 Hz)₅7.31-7.40 (3H₅ m), 7.51 (IH₅ dd, J= 8.9, 2.6 Hz)₅ 7.77 (IH₅ d, J= 2.6 Hz)₅7.99 (IH₅ d, J=

3.2 Hz)₅ 8.44 (IH₅ br s), 8.68 (IH₅ s), 9.81 (IH₅ br s). Synthesis Example 266

Production of 4-[2-cWoro-4-({5-[2-(2-hydroxye1hoxy)ethyl]-5H-pyrrolo[3₅2-d]pyrimidin-4- yl} amino)phenoxy] -N-(4-methylphenyl)piperidine- 1 -carboxamide hydrochloride

The title compound (190 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 262 (ii) using 2-[2-(4-{[3-chloro-4-(piperidin-4- yloxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (305 mg), 10% aqueous sodium carbonate solution (10 mL), ethyl acetate (15 mL), tetrahydrofuran (5 mL) and 4-methylphenyl isocyanate (67 mg). 1H-NMR (DMSOd₆) δ 1.60-1.75 (2H, m), 1.90-2.03 (2H, m), 2.23 (3H, s), 3.34-3.51 (6H, m), 3.69-3.80 (2H, m), 3.84 (2H, t, J= 4.5 Hz)₅4.694.84 (3H₅ m), 6.67 (IH₅ d, J= 3.0 Hz)₅7.03 (2H₅ d, J= 8.5 Hz)₅7.31-7.39 (3H₅ m), 7.51 (IH₅ dd, J= 8.9, 2.7 Hz)₅ 7.76 (IH₅ d, J= 2.7 Hz)₅7.99 (IH₅ d, J= 3.0 Hz)₅ 8.50 (IH₅ br s), 8.68 (IH₅ s), 9.82 (IH₅ br s). Synthesis Example 267

Production of tert-butyl 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3 ,2-d]pyrimidin-

4-yl}amino)phenoxy]benzoate hydrochloride

(i) Production of tert-butyl 4-{4-[(5-{2-[2-(i3enzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3₅2-d]pyrirnidin-

4-yl)amino]-2-chlorophenoxy}benzoate

A mixture of 2-[2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (1.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)benzoate (1.35 g) and isopropyl alcohol (30 mL) was stirred at 80⁰C overnight. The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate). The object fraction was concentrated under reduced pressure and the residue was crystallized from ethyl acetate-diethyl ether to give the title compound (1.54 g) as a white powder. 1H-NMR (CDCl₃) δ 1.59 (9H₅ s), 3.93-3.99 (2H, m), 4.05-4.11 (2H, m), 4.464.52 (2H, m), 4.55- 4.61 (2H, m), 6.64 (IH, d, J= 3.2 Hz)₅ 6.82-6.90 (3H, m)₅ 7.22 (IH₅ d, J= 3.2 Hz), 7.30-7.40 (3H, m)₅ 7.47-7.54 (IH₅ m), 7.76-7.81 (2H₅ m), 7.90 (IH, d, J= 2.6 Hz)₅7.94 (2H₅ d, J= 9.1 Hz), 8.51 (IH₅ s)₅ 8.78 (IH₅ br s).

(ϋ) Production of tert-butyl 4-[2-chloro4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-ρyrrolo[3,2- d]pyrimidin-4-yl} amino)phenoxy]benzoate hydrochloride tert-Butyl 4-{4-[(5-{2-[2-(penzoyloxy)e1hoxy]emyl}-5H-pyπ-olo[3₅2-d]pyrirrήdm yl)amino]-2-chlorophenoxy}benzoate (189 mg) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (1 mL), IN aqueous sodium hydroxide solution (0.6 mL) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 — » 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and IN hydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (163 mg) as a white powder. 1H-NMR (DMSO-de) δ 1.54 (9H₅ s), 3.41-3.52 (4H₅ m), 3.85 (2H₅ m)₅4.84 (2H, m), 6.71 (IH, d, J=

3.2 Hz)₅ 7.02 (2H₅ d, J= 8.9 Hz)₅7.36 (IH, d, J= 8.9 Hz)₅ 7.69 (IH₅ dd, J= 8.9, 2.4 Hz)₅7.93 (2H₅ d₅ J= 8.9 Hz), 8.00 (IH, d, J= 2.4 Hz), 8.04 (IH, d, J= 3.2 Hz), 8.75 (IH, s), 10.00 (IH, br s).

Synthesis Example 268

Production ofN-(tert-butyl)-4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-yl}amino)phenoxy]benzamide hydrochloride

Trifluoroacetic acid (10 mL) was added to tert-butyl 4-{4-[(5-{2-[2- φenzoyloxy)ethoxy]ethyl}-5H-pyrrolo[3,2-d]pyrM (1.26 g), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, 4N hydrochloric acid/ethyl acetate solution was added, and the mixture was concentrated again under reduced pressure. The obtained residue was crystallized from ethyl acetate to give the title compound (1.16 g) as a white powder.

¹H-NMR (DMSOd₆) δ 3.76-3.83 (2H, m), 3.92 (2H, t, J= 4.4 Hz), 4.264.34 (2H, m), 4.89 (2H, m), 6.63 (IH, d, J= 3.4 Hz), 6.98 (2H, d, J= 8.8 Hz), 7.27 (IH, d, J= 8.8 Hz), 7.41-7.50 (2H, m), 7.55-

7.73 (4H, m), 7.92-8.03 (4H, m), 8.66 (IH, s), 9.91 (IH, br).

(ϋ) Production ofN-(tert-butyl)-4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2- d]pyrirrddin-4-yl}arnino)phenoxy]benzamide hydrochloride

A mixture of 4-{4-[(5-{2-[2-(^nzoyloxy)e1b.oxy]e1hyl}-5H-pyrrolo[3,2-d]pyrirnidin-4- yl)amino]-2-chlorophenoxy} benzoic acid hydrochloride (183 mg), 2-methylpropan-2-amine (0.038 mL), l-etiiyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (69 mg), 1- hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL) and N,N- dimethylformamide (3 mL) was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 -> 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (1 mL), IN aqueous sodium hydroxide solution (0.6 mL) was added and the mixture was stirred at room temperature for 3 days. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100 — > 10:90). The object fraction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate-ethanol, and IN hydrochloric acid/ethyl acetate solution (0.3 mL) was added. The solvent was evaporated under reduced pressure and the obtained residue was crystallized from ethanol-ethyl acetate to give the title compound (118 mg) as a white powder. 1H-NMR (DMSCKI₆) δ 1.37 (9H, s), 3.41-3.52 (4H, m), 3.85 (2H, m), 4.84 (2H₅ m), 6.71 (IH, d, J= 3.2 Hz), 6.97 (2H, d, J= 8.8 Hz), 7.29 (IH, d, J= 8.8 Hz), 7.67 (IH, dd, J= 8.8, 2.5 Hz), 7.72 (IH, s), 7.85 (2H, d, J= 8.8 Hz), 7.99 (IH, d, J= 2.5 Hz), 8.04 (IH, d, J= 3.2 Hz), 8.75 (IH, s), 10.00 (IH, br s).

Synthesis Example 269

Production of 4-[2-cMoro4-({5-[2-(2-hydroxye1hoxy)ethyl]-5H-pyrrolo[3,2-d]pyriinidin-4- yl}amino)phenoxy]-N-(2,2-dimethylpropyl)benzamide

The title compound (140 mg) was obtained as a white powder by the method in the same 5 manner as in Synthesis Example 268 (ii) using 4-{4-[(5-{2-[2-(benzoyloxy)ethoxy]ethyl}-5H- pyrrolo[3,2-d]pyrimidin-4-yl)amino]-2-chlorophenoxy} benzoic acid hydrochloride (183 mg), neopentylamine (0.042 mL), 1 -ethyl-3 -(3 -dimethylarrώiopropyl)carbodiirnide hydrochloride (69 mg), 1-hydroxybenzotriazole monohydrate (55 mg), triethylamine (0.050 mL), N₉N- dimethylformamide (3 mL), methanol (5 mL), tetrahydrofuran (1 mL) and IN aqueous sodium i o hydroxide solution (0.6 mL).

¹H-NMR (DMSOd₆) δ 0.90 (9H, s), 3.10 (2H, d, J= 6.4 Hz)₅3.42-3.52 (4H, m), 3.86 (2H, t, J= 4.6 Hz), 4.83 (2H, t, J= 4.6 Hz), 6.71 (IH, d, J= 2.9 Hz), 7,01 (2H, d, J= 8.5 Hz), 7.32 (IH, d, J= 8.8 Hz), 7.66 (IH, dd, J= 8.8, 2.2 Hz), 7.91 (2H, d, J= 8.5 Hz), 7.99 (IH, d, J= 2.2 Hz), 8.03 (IH, d, J= 2.9 Hz), 8.32 (IH, t, J= 6.4 Hz), 8.75 (IH, s), 9.95 (IH, br s).

15 Synthesis Example 270

Production of 4-[2-cMoro4-({5-[2-(2-hydroxye1hoxy)e1hyl]-5H-pyrrolo[3,2-d]pyrimidin-4- yl}amino)phenoxy]-N-(2,2,2-trMuoroethyl)piperidine-l-carboxamide hydrochloride

The title compound (101 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 264 using l,r-carbonylbis(lH-imidazole) (97 mg), 2,2,2- trifluoroethylamine (0.048 mL), 2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (244 mg), triethylamine (0.123 mL) and IN aqueous sodium hydroxide solution (0.6 mL).

¹H-NMRpMSO-(I₆) δ 1.53-1.68 (2H,m), 1.84-1.98 (2H, m), 3.25-3.70 (8H,m), 3.77-3.92 (4H, m), 4.66-4.77 (IH, m), 4.79 (2H, t, J= 4.8 Hz), 6.67 (IH₅ d, J= 3.1 Hz), 7.23 (IH, t, J= 6.2 Hz), 7.33 (IH, d, J= 9.0 Hz), 7.50 (IH, dd, J= 9.0, 2.6 Hz), 7.76 (IH, d, J= 2.6 Hz), 7.99 (IH, d, J= 3.1 Hz), 8.68 (IH, s), 9.78 (IH, brs).

Production of 2,2,2-trMuoroethyl 4-[2-chloro-4-({5-[2-(2-hydroxyethoxy)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-yl} amino)phenoxy]piperidine- 1 -carboxylate hydrochloride The title compound (135 mg) was obtained as a white powder by the method in the same manner as in Synthesis Example 264 using l,r-carbonylbis(lH-imidazole) (97 mg), 2,2,2- trifluoroethanol (0.044 mL), 2-[2-(4-{[3-chloro-4-(piperidin-4-yloxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate dihydrochloride (244 mg), triethylamine (0.123 mL) and IN aqueous sodium hydroxide solution (0.6 mL). 1H-NMR (DMSO-ctø δ 1.62-1.77 (2H, m), 1.89-2.02 (2H, m), 3.38-3.52 (6H, m), 3.58-3.73 (2H, m), 3.83 (2H, t, J= 4.7 Hz), 4.67-4.85 (5H, m), 6.68 (IH₅ d, J= 2.9 Hz), 7.34 (IH, d, J= 9.0 Hz), 7.51

(IH, dd, J= 9.0, 2.5 Hz), 7.76 (IH, d, J= 2.5 Hz), 7.99 (IH, d, J= 2.9 Hz), 8.68 (IH, s), 9.82 (IH, br s).

Synthesis Example 272

Production of N-(tert-butyl)-4-(2-cUoro4-{[5-(2-{[(me%lsulfonyl)acetyl]amino}ethyl)-5H- pyrrolo[3,2-d]pyriniidin-4-yl]amino}phenoxy)piperidine-l-carboxainide tert-Butyl 4-(2-cWoro-4-{[5-(2-{[(me%lsulfonyl)acetyl]amino}e%l)-5H-pyrrolo[3,2- d]pyrimidin-4-yl]ainino}phenoxy)piperidine-l-carboxylate (120.0 mg) was dissolved in methanol (4.0 mL), 4N hydrochloric acid/ethyl acetate (5 mL) was added, and the mixture was stirred for 5 hrs. 8N Aqueous sodium hydroxide solution (5 mL) and water (10 mL) were added, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated. The residue was added to the reaction system, wherein l,r-carbonylbis(lH- imidazole) (48.5 mg) and 2-methylpropan-2-amine (22.0 mg) were dissolved in tetrahydrofuran (5.0 mL), and the mixture was stirred for 1 hr. Triethylamine (1.0 mL) was further added dropwise and the mixture was stirred for 1 hr. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetatemethanol^lOOiO -> ethyl acetate:methanol=80:20). Crystallization from diethyl ether/ethyl acetate gave the title compound (17.9 mg) as crystals. 1H-NMRpMSO-Cl₆) δ 1.26 (9H, s), 1.50-1.70 (2H, m), 1.81-1.95 (2H, m), 3.10 (3H, s), 3.11-3.65 (6H, m), 4.05 (2H, s), 4.45-4.65 (3H₅ m), 5.82 (IH, s), 6.47 (IH, d, J= 3 Hz), 7.22 (IH, d, J= 9 Hz), 7.55-7.58 (2H, m), 7.75 (IH, d, J= 3 Hz), 8.27 (IH, s), 8.48 (IH, s), 8.66 (IH, m). 5 Synthesis Example 273

Production of N-{2-[4-({3-cUoro-4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrirnidin-5-yl]ethyl}-N'-methoxyurea

To a solution of N,N'-carbonyldiimidazole (187 mg) inN,N-dimethylformamide (2 mL) i o were added 0-methylhydroxylamine hydrochloride (96 mg) and triethylamine (0.27 mL) under ice- cooling, and the mixture was stirred at room temperature for 30 min. A solution of 5-(2- aminoemyl)-N-{3-cMoro-4-[3-(Mfluorome1hy^ amine dihydrochloride (200 mg) inNjN-dimethyrformamide (5 mL) was added. The reaction mixture was stirred at room temperature for 22 hrs, aqueous sodium hydrogen carbonate and brine

15 were added under ice-cooling, and the mixture was extracted twice with ethyl acetate. The organic layers were collected, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0 — >^■ 80:20) and further recrystallized from ethyl acetate/dϋsopropyl ether to give the title compound (116 mg) as crystals. 0 ¹H-NMR (CDCl₃) δ: 3.6-3.7 (2H, m), 3.70 (3H, s), 4.54.6 (2H, m), 6.14 (IH, br s), 6.63 (IH, d, J= 3.0 Hz), 7.05 (IH₅ d, J= 9.0 Hz), 7.1-7.5 (5H, m), 7.65-7.75 (IH, m), 8.02 (IH, d, J= 2.7 Hz), 8.46 (IH, s), 8.52 (IH, s). Synthesis Example 274

5 Production of N-{2-[4-({3-cMoro4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrinτidin-5-yl]ethyl}-N'-(2-methoxyethyl)urea

The title compound (147 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 273 using 5-(2-aminoethyl)-N-{3-chloro-4-[3-

(trMuoromethyl)phenoxy]phenyl}-5H-pyπ-olo[3,2-d]pyrirmdin-4-amine dihydrochloride (200 mg), i o 2-methoxyethylamine (87 mg) and N,N-dimethylformamide (3 mL).

¹H-NMR (DMSO-de) δ: 3.05-3.15 (2H, m), 3.12 (3H, s), 3.2-3.5 (4H, m), 4.55-4.65 (2H, m), 6.42 (IH, br s), 6.56 (IH, br s), 6.68 (IH, d, J= 1.8 Hz), 7.25-7.35 (2H, m), 7.36 (IH, d, J= 8.7 Hz), 7.52 (IH, d, J= 8.1 Hz), 7.64 (IH, d, J= 9.0 Hz), 7.76 (IH, d, J= 9.0 Hz), 7.95-8.05 (2H, m), 8.75 (IH, s), 9.12 (IH, s).

15 Synthesis Example 275

Production of 3-[4-({3-cUoro-4-[3-(tMuorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]propanenitrile

The title compound (2.02 g) was obtained as a powder by the reaction in the same manner as in Synthesis Example 171 using 4-cWoro-5H-pyrrolo[3,2-d]pyrimidine (3.07 g), N₅N- 5 dimethylformarnide (30 mL), potassium carbonate (4.15 g), 3-bromopropionitrile (3.48 g), 3- chloro-4-[3-(trifluorome1hyl)phenoxy]aniline (2.26 g) andisopropyl alcohol (20 mL). 1H-NMR (DMSOd₆) δ: 3.01 (2H, t, J= 6.4 Hz)₅4.83 (2H₅1, J= 6.4 Hz)₅6.58 (IH₅ s), 7.2-7.3 (2H₅ m), 7.31 (IH₅ d, J= 8.4 Hz)₅7.47 (IH₅ d, J= 7.5 Hz)₅7.55-7.7 (2H₅ m), 7.7-7.8 (IH₅ m), 7.87 (IH₅ s), 8.37 (IH₅ S)₅ 8.76 (IH₅ S). i o Synthesis Example 276

Production of 6-{3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}-8₅9-dihydro-3₅5₅6₅9a- tetraazabenzo[αl]azulen-7(6H)-irriine dihydrochloride

12N Hydrogen chloride/ethanol (3 mL) was added to 3-[4-({3-chloro-4-[3-

15 (trffluoromethyl)phenoxy]phenyl}an^ (200 mg) under ice-cooling, and the mixture was stirred at O⁰C for 2 hrs. The reaction mixture was concentrated and the residue was washed with ethyl acetate and diisopropyl ether to give the title compound (161 mg) as a powder. 1H-NMR (DMSO-d_δ) δ: 3.55-3.65 (2H₅ m), 4.7-4.8 (2H₅ m), 6.75-6.8 (IH₅ m), 7.4-7.5 (2H₅ m), 7.5- 0 7.6 (2H₅ m), 7.65-7.75 (IH, m), 7.94 (IH, s), 8.05-8.1 (IH, m), 8.59 (IH, s), 9.37 (IH₅ s), 11.29 (IH₅ S).

Synthesis Example 277

Production of N-{2-[4-({3-cMoro4-[3-(trifluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- 5 d]pyrimidin-5-yl]eliiyl}-N'-methylguanidine dihydrochloride

To a solution of N-methyl-N,N'-bis(tert-butoxy carbonyty-lH-pyrazole-l-carboxamidine (138 mg) and ethyldiisopropylamine (0.16 mL) in acetonitrile (4 mL) was added 5-(2-aminoethyl)- N-{3-ctøoro^-[3-(trifluoromethyl)phem dihydrochloride (200 mg), and the mixture was stirred at room temperature for 4 days. Under ice- j o cooling, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=80:20 -> 100:0). The obtained product was dissolved in ethyl acetate, 4N hydrochloric acid/ethyl acetate was added, and the mixture was stirred at room temperature for 22 hrs. The precipitate was collected by filtration,

15 and washed with ethyl acetate and diisopropyl ether to give the title compound (98 mg) as a powder. 1H-NMR (DMSO-ds) δ: 2.57 (3H, d, J= 3.3 Hz), 3.5-3.7 (2H, m), 4.8-4.9 (2H, m), 6.72 (IH, s), 7.25-7.3 (2H, m), 7.38 (IH, d, J= 9.0 Hz), 7.4-7.6 (3H, m), 7.6-7.75 (3H, m), 8.01 (2H, d, J= 8.1 Hz), 8.75 (IH, s), 10.15 (IH, s). Synthesis Example 278

Production of 2-(2-{4-[(3-cMoro-4-{4-[3-(lH-imida2X3l-l-yl)propyl]phenoxy}phenyl)amino]-5H- pyiτolo[3,2-d]pyrimidin-5-yl}ethoxy)efhanol dihydrochloride (i) Production of 3-chloro4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}nitrobenzene 5 To a solution of 4-[3-(lH-imidazol-l-yl)propyl]phenol (405 mg) and 3-chloro-4- fluoronitrobenzene (370 mg) inN,N-dirnethylformamide (4 mL) was added potassium carbonate (415 mg), and the mixture was stirred at room temperature for 16 hrs. Under ice-cooling, water was added and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel i o column chromatography (eluent, ethyl acetate:hexane=80:20 -> 100:0) to give the title compound (669 mg) as an oil.

¹H-NMR (CDCl₃) δ: 2.1-2.25 (2H, m), 2.65 (2H, t, J= 7.6 Hz), 3.98 (2H, t, J= 6.9 Hz), 6.86 (IH, d, J= 9.0 Hz), 6.93 (IH, s), 7.02 (IH, d, J= 8.6 Hz), 7.09 (IH, s), 7.21 (IH, d, J= 8.6 Hz), 7.47 (IH, s), 8.04 (IH, dd, J= 9.0, 2.7 Hz), 8.38 (IH, d, J= 2.7 Hz).

15 (ii) Production of 3-cMoro4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}aniline

To a solution of 3-chloro-4-{4-[3-(lH-imidazol-l-yl)propyl]ρhenoxy} nitrobenzene (669 mg) in methanol (7 mL) was added 5% Pt/C (140 mg), and the mixture was stirred under hydrogen atmosphere at room temperature for 16 hrs. 5% Pt/C was filtered off and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (eluent, ethyl acetate:hexane=80:20 -» 100:0) and further washed with diethyl ether and hexane to give the title compound (277 mg) as a powder.

¹H-NMR (CDCl₃) δ: 2.09 (2H, quintet, J= 7.2 Hz), 2.56 (2H, t, J= 7.2 Hz), 3.67 (2H, br s), 3.93 (2H, t, J= 7.2 Hz), 6.56 (IH, dd, J= 8.4, 2.7 Hz), 6.75-6.95 (5H, m), 7.0-7.1 (3H, m), 7.45 (IH₅ s). (iϋ) Production of 2-(2-{4-[(3-cWoro4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}phenyl)arnino]- 5H-pyrrolo[3,2-d]pyriniidin-5-yl}ethoxy)ethanol diliydrochloride

The title compound (99 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 138 (ii) and (iϋ) using 2-[2-(4-cUoro-5H-pyrrolo[3,2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (207 mg), 3-chloro-4-{4-[3-(lH-imidazol-l-yl)propyl]phenoxy}aniline (197 mg) andte1rahydroruran(4 rnL).

¹H-NMR (DMSOd₆) δ: 2.1-2.3 (2H, m), 2.5-2.7 (2H, m), 3.4-3.6 (2H, m), 3.8-3.9 (2H, m), 4.23 (2H, t, J= 6.8 Hz), 4.87 (2H, s), 6.71 (IH, d, J= 2.4 Hz), 6.92 (2H, d, J= 8.1 Hz), 7.14 (IH, d, J= 8.1 Hz), 7.25 (2H, d, J= 8.4 Hz), 7.6-7.7 (IH, m), 7.70 (IH, s), 7.83 (IH, s), 7.94 (IH, s), 8.04 (IH, d, J= 3.0 Hz), 8.73 (IH, s), 9.22 (IH, s). Synthesis Example 279

Production of 2-(2-{4-[(3-cUoro-4-{4-[4-(lH-l,2,3-Mazol-l-yl)butyl]phenoxy}phenyl)amino]-5H- pyπrolo[3,2-d]pyrirnidin-5-yl}ethoxy)ethanol

(i) Production of 3-chloro4-{4-[4-(lH-l_>2,3-triazol-l-yl)butyl]phenoxy}nitrobenzene The title compound (721 mg) was obtained as an oil by the reaction in the same manner as in Synthesis Example 278 (i) using 4-[4-(lH-l,2,3-triazol-l-yl)butyl]ρhenol (435 mg), 3-chloro-4- fluoronitrobenzene (370 mg) andN,N-dimethyh^cormamide (4 mL).

¹H-NMR (CDCl₃) δ: 1.6-1.75 (2H, m), 1.9-2.05 (2H, m), 2.68 (2H, t, J= 7.4 Hz), 4.43 (2H, t, J= 7.2 5 Hz), 6.85 (IH, d, J= 9.2 Hz), 7.00 (2H, d, J= 8.8 Hz), 7.21 (2H₅ d, J= 8.8 Hz), 7.53 (IH, s), 7.72 (IH, s), 8.04 (IH₅ dd, J= 2.6₅9.2 Hz)₅ 8.37 (IH₅ d, J= 2.6 Hz).

(ϋ) Production of 3-chloro4-{4-[4-(lH-l₅2₅3-triazol-l-yl)butyl]phenoxy}aniline

The title compound (626 mg) was obtained as an oil by the reaction in the same manner as in Synthesis Example 278 (ii) using 3-chloro-4-{4-[4-(lH-l₅2₅3-triazol-l- o yl)butyl]phenoxy} nitrobenzene (711 mg) and ethyl acetate (10 mL).

¹H-NMR (CDCl₃) δ: 1.55-1.7 (2H₅ m)₅ 1.8-2.0 (2H₅ m), 2.60 (2H₅1, J= 7.5 Hz)₅3.65 (2H₅ br s)₅4.39

(2H₅1, J= 7.2 Hz), 6.55 (IH₅ dd, J= 8.7, 2.7 Hz)₅6.75-6.85 (3H₅ m), 6.87 (IH₅ d, J= 8.4 Hz)₅7.04

(2H₅ d, J= 8.4 Hz), 7.49 (IH, d, J= 1.0 Hz), 7.69 (IH₅ d, J= 1.0 Hz).

(iϋ) Production of 2-(2-{4-[(3-chloro-4-{4-[4-(lH-l ₅2,3-triazol-l-yl)butyl]phenoxy}phenyl)amino]- 5H-pyrrolo[3₅2-d]pyrirnidin-5-yl}ethoxy)ethanol

The title compound (293 mg) was obtained as a powder by the reaction in the same manner as in Synthesis Example 139 (ii) and (iϋ) using 2-[2-(4-cUoro-5H-pyrrolo[3₅2-d]pyrimidin-5- yl)ethoxy]ethyl benzoate (346 mg), 3-chloro-4-{4-[4-(lH-l₅2,3-triazol-l-yl)butyl]phenoxy}aniline

(405 mg) and isopropyl alcohol (5 mL). 1H-NMR (DMSO-de) δ: 1.55-1.7 (2H₅ m)₅ 1.85-2.0 (2H₅ m), 2.62 (2H₅1, J= 7.2 Hz)₅3.7-3.75 (2H, m), 3.75-3.8 (2H, m), 4.02 (2H₅ t, J= 4.2 Hz), 4.39 (2H, t, J= 6.9 Hz), 4.56 (2H, t, J= 4.2 Hz)₅ 6.63

(IH₅ d, J= 3.0 Hz)₅ 6.88 (2H₅ d, J= 8.7 Hz), 6.98 (IH₅ d, J= 8.4 Hz), 7.08 (2H, d, J= 8.7 Hz), 7.21

(IH, d, J= 3.3 Hz), 7.50 (IH, s), 7.54 (IH, dd, J= 8.7, 2.7 Hz), 7.87 (IH, d, J= 2.7 Hz)₅ 7.69(1H₅ s), 8.51 (IH, s), 8.73 (IH, s).

Synthesis Example 280

Production of 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trifluoromethoxy)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyriniidin-5-yl]e&^ methanesulfonate

The title compound (1.0 g) was obtained as colorless crystals by the reaction in the same manner as in Synthesis Example 256 using 2-(methylsulfonyl)-N-{2-[4-({3-methyl-4-[3- (trffluoromethoxy)phenoxy]phenyl}arrii^^ mg), ethyl acetate (4.5 mL) and methanesulfonic acid (0.114 mL).

¹H-NMR (DMSOd₆) δ 2.19 (3H, s), 2.32 (3H, s), 3.05 (3H, s), 3.55 (2H, q, J= 6 Hz), 4.06 (2H, s), 4.68 (2H, t, J= 6 Hz), 6.65 (IH, d, J= 3 Hz), 6.93 (2H, m), 7.12 (2H, m), 7.4-7.6 (3H, m), 7.92 (IH, d, J= 3 Hz), 8.70 (2H₅ m), 9.84 (IH, br s). Synthesis Example 281

Production of N-[2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl]arnMo}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)ethyl]-2-methyl-2-(methylsulfonyl)propanamide

To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (487 mg), 2-methyl-2-(methylsulfonyl)propanoic 5 acid (249 mg) and 1-hydroxybenzotriazole (225 mg) inN^-dimeihylformamide (5.0 mL) were added triethylamine (0.69 mL) and l-ethyl-3-(3-dime1hylaminopropyl)carbodiimide hydrochloride (316 mg) under ice-cooling, and the mixture was stirred at room temperature for 15 hr . Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under i o reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0->90:10) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (419 mg) as colorless crystals. 1H-NMR (CDCl₃) δ: 1.70 (6H, s), 2.93 (3H, s), 3.60-3.80 (2H, m), 4.404.60 (2H, m), 6.46 (IH, d, J = 2.8 Hz), 6.85-7.00 (2H, m), 7.00-7.15 (2H₅ m),7.15-7.30 (2H, m), 7.30-7.40 (IH, m), 7.85-7.95 is (IH, m), 8.00-8.05 (IH, m), 8.36 (IH, br s), 8.54 (IH, s). Synthesis Example 282

Production of N-[2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl]anτino}-5H-pyiτolo[3,2-d]pyrimidin- 5-yl)ethyl]-2-(methylsulfonyl)propanamide To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyrrolo[3,2-d]pyrimidin-4-ainine dihydrochloride (200 mg), 2-chloropropanoic acid (67 mg) and 1- hydroxybenzotriazole (90 mg) inN,N-dimethylformamide (4.0 mL) were added triethylamine (0.29 mL) and l-ethyl-3-(3-dimethylaminopropyl)carbodikπide hydrochloride (126 mg) under ice- 5 cooling, and the mixture was stirred at room temperature for 17 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved in N,N-dimethylformamide (2 mL), sodium methanesuhinic acid (420 mg) and pyridine (0.40 mL) were added, and the mixture was stirred at 7O⁰C for 2 days. After cooling to i o room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0->95:5) and further recrystallized from ethyl acetate/dϋsopropyl ether to give the title compound (97 mg) as colorless crystals. is ¹H-NMR (CDCl₃) δ: 1.71 (3H, d, J = 7.2 Hz), 2.98 (3H, s), 3.65-3.75 (2H, m), 3.81 (IH, q, J = 7.2 Hz), 4.454.55 (2H, m), 6.61 (IH, d, J = 3.3 Hz), 6.85-6.90 (IH, m), 6.90-6.95 (IH, m), 7.00-7.10 (2H, m), 7.20-7.30 (IH, m), 7.30-7.40 (IH, m), 7.75-7.85 (IH, m), 7.97 (IH, d, J = 2.4 Hz), 8.28 (IH, s), 8.51 (IH, s). Synthesis Example 283

Production of N-[2-(4-{[3-cUoro4-(3-cMorophenoxy)phenyl]anτino}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)ethyl]-2-(isopropylsulfonyl)acetamide

(i) Production of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethyl]-2-(isopropylthio)acetarnide

5 To a solution of 5-(2-arninoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyrrolo[3,2-d]pyrirnidin-4-arnine dihydrochloride (300 mg), chloroacetic acid (87 mg) and 1- hydroxybenzotriazole (135 mg) inN,N-dimethylformamide (5.0 mL) were added triethylamine (0.43 mL) and l-ethyl-3-(3-dimelhylaminopropyl)carbodiimide hydrochloride (189 mg) under ice- cooling, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction i o mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was dissolved inN,N-dimethylformamide (2 mL)/tetrahydrofuran (4 mL), sodium propane- 2-thiolate (605 mg) was added, and the mixture was stirred at room temperature for 6 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl

15 acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0->95:5) to give the title compound (201 mg) as a white powder. 1H-NMR (CDCl₃) δ: 1.24 (6H, d, J = 6.9 Hz), 2.80-2.90 (IH, m), 3.33 (2H, s), 3.60-3.70 (2H, m), 0 4.45-4.55 (2H, m), 6.62 (IH, d, J = 3.3 Hz), 6.85-6.90 (IH, m), 6.95-7.00 (IH, m), 7.00-7.05 (IH₅ m), 7.07 (IH, d, J = 8.7 Hz), 7.20-7.30 (2H, m), 7.40-7.50 (IH, m), 7.73 (IH, dd, J = 2.4, 8.7 Hz), 8.05 (IH, d, J = 2.4 Hz), 8.51 (IH, s). (ϋ) Production of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyriniidin-5-yl)ethyl]-2-(isopropylsulfonyl)acetamide

To a solution of N-[2-(4-{[3-cUoro-4-(3-cUorophenoxy)phenyl]anτino}-5H"pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(isopropylthio)acetarnide in methanol (6 mL)/water (1.5 mL) was added OXONE® monopersulfate compound (339 mg), and the mixture was stirred at room temperature for 21 hr. Water was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from dichloromethane/methanol/dϋsopropyl ether to give the title compound (173 mg) as pale-yellow crystals. 1H-NMR (DMSOd₆) δ: 1.23 (6H, d, J = 6.9 Hz), 3.40-3.65 (3H, m), 4.03 (2H, s), 4.50-4.70 (2H, m), 6.58 (IH, s), 6.90-6.95 (IH, m), 6.99 (IH, s), 7.15-7.25 (IH, m), 7.30 (IH, d, J = 8.7 Hz), 7.40- 7.50 (IH, m), 7.65-7.75 (IH, m), 7.79 (IH, s), 7.92 (IH, s), 8.53 (IH, s), 8.70-8.80 (IH, m), 9.28 (lH, br s). Synthesis Example 284

Production of N-[2-(4-{[3-cWoro-4-(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pvrimidin-

5-yl)ethyl]-2-(ethylsulfonyl)acetamide

(i) Production of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(ethylthio)acetamide Using 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (200 mg), ethylthioacetic acid (99 mg), 1- hydroxybenzotriazole (123 mg), triethylamine (0.57 mL), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (173 mg) andN,N-dimethylformamide (4.0 mL) and in the same manner as in Example A-I, the title compound (186 mg) was obtained as a white powder.

¹H-NMR (CDCl₃) δ: 1.24 (3H, t, J = 7.5 Hz), 2.52 (2H, q, J = 7.5 Hz), 3.32 (2H, s), 3.60-3.70 (2H₅ _m)_s 4.45-4.55 (2H, m), 6.62 (IH, d, J = 3.0 Hz)₅ 6.88 (IH, d, J = 8.1 Hz), 6.95-7.00 (IH, m), 7.00- 7.10 (2H, m), 7.15-7.25 (IH, m), 7.40-7.50 (IH, m), 7.70-7.80 (IH, m), 8.05-8.10 (IH, m), 8.50 (IH, s), 8.51 (IH, s).

(ϋ) Production of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(ethylsulfonyl)acetamide

Using N-[2-(4-{[3-chloro4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(ethylthio)acetamide (180 mg), OXONE® monopersulfate compound (322 mg) and methanol (6 mL)/water (1.2 mL) and in the same manner as in Example A-3 (ϋ), the title compound (149 mg) was obtained as colorless crystals.

¹H-NMR (DMSOd₆) δ: 1.21 (3H, t, J = 7.2 Hz), 3.22 (2H, q, J - 7.2 Hz), 3.45-3.55 (2H₅ m), 4.03 (2H, s), 4.554.65 (2H, m), 6.55-6.60 (IH, m), 6.90-6.95 (IH, m), 6.99 (IH, s), 7.15-7.20 (IH, m), 7.29 (IH, d, J = 8.7 Hz), 7.41 (IH, t, J = 8.2 Hz), 7.65-7.75 (IH, m), 7.75-7.80 (IH, m), 7.93 (IH₅ s), 8.52 (IH₅ s), 8.72 (IH, br s), 9.22 (IH, br s). Synthesis Example 285

Production of N-[2-(4-{[3-cUoro-4-(3-cMorophenoxy)phenyl]an±io}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)ethyl]-N-methyl-2-(methylsulfonyl)acetamide

(i) Production of tert-butyl [2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- 5 d]pyrirnidin-5-yl)ethyl]methylcarbamate

A mixture of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin~5- yl)ethyl]methylcarbamate (2.56 g), 3-chloro-4-(3-chlorophenoxy)aniline (2.51 g) andisopropyl alcohol (25 mL) was stirred at 8O⁰C for 18 hr. After cooling to room temperature, the mixture was stirred for 5 hr. The precipitate was collected by filtration, and washed with dϋsopropyl ether to i o give the title compound (3.72 g) as a white powder.

¹H-NMR (CDCl₃) δ: 1.52 (9H, s), 3.01 (3H, s), 3.50-3.60 (2H, m), 4.40-4.50 (2H, m), 6.60 (IH, d, J - 3.0 Hz), 6.85-6.95 (IH, m), 6.95-7.00 (IH, m), 7.00-7.05 (IH, m), 7.07 (IH, d, J = 9.0 Hz), 7.15- 7.25 (2H, m), 7.90 (IH, d, J = 9.0 Hz), 8.01 (IH, br s), 8.52 (IH, s), 8.83 (IH, s). (ϋ) Production of N-[3-cMoro4-(3-cMorophenoxy)phenyl]-5-[2-(methylamino)ethyl]-5H-

15 pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride

A mixture of tert-butyl [2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]methylcarbamate (3.72 g) and 10% (WAV) hydrochloric acid/methanol (30 mL) was stirred at 65°C for 24 hr. The reaction mixture was concentrated under reduced pressure, and the precipitate was collected by filtration, and washed with diethyl ether to 0 give the title compound (2.70 g) as pale-yellow crystals. ¹H-NMR (DMSOd₆) δ: 2.50-2.60 (3H, m), 3.30-3.50 (2H, m), 5.00-5.20 (2H, m), 6.75 (IH, d, J =

3.0 Hz), 6.90-7.00 (IH₅ m), 7.02 (IH, s), 7.21 (IH, d, J = 7.8 Hz), 7.32 (IH, d, J = 8.7 Hz), 7.44 (IH, t, J = 8.1 Hz), 7.66 (IH, d, J = 8.7 Hz), 7.93 (IH, s), 8.07 (IH, d, J = 3.0 Hz), 8.73 (IH, s), 9.10-9.30

(2H, m), 10.17 (IH, br s). 5 (iϋ) Production of N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)e1iiyl]-N-me1hyl-2-(me1hylsulfonyl)acetanτide

Using N-[3-cMoro4-(3-cMorophenoxy)phenyl]-5-[2-(me1hylamino)ethyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (200 mg), methylsulfonylacetic acid (83 mg), 1- hydroxybenzotriazole (87 mg), triethylatnine (0.28 mL), l-ethyl-3-(3- i o dime1hylaminopropyl)carbodiimide hydrochloride (123 mg) and N,N-dimethylfomiamide (5.0 mL) and in the same manner as in Example A-I, the title compound (164 mg) was obtained as colorless crystals.

¹H-NMR(CDCl₃) δ: 3.17 (3H, s), 3.33 (3H, s), 3.70-3.85 (2H, m), 4.17 (2H, s), 4.45-4.55 (2H, m),

6.63 (IH, d, J = 3.0 Hz), 6.85-6.95 (2H, m), 7.00-7.10 (2H, m),7.20-7.30 (2H, m), 7.82 (IH, dd, J = is 2.7 Hz, 9.0 Hz), 7.92 (IH, d, J = 2.7 Hz), 8.44 (IH, s), 8.52 (IH, s).

Synthesis Example 286

Production of 2-(tert-butylsulfonyl)-N-[2-(4-{[3-cUoro-4-(3-cUorophenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide © Production of 2-(tert-butylMo)-N-[2-(4-{[3-chloro-4-(3-cMorophenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide

To a solution of 5-(2-aminoethyl)-N-[3-chloro-4-(3-chlorophenoxy)phenyl]-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg), chloroacetic acid (58 mg) and 1- 5 hydroxybenzotriazole (90 mg) in N,N-ditnethylformamide (4.0 mL) were added triethylamine (0.29 mL) and l-ethyl-3-(3-dime1hylarriinopropyl)carbodrirnide hydrochloride (126 mg) under ice- cooling, and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the i o residue was dissolved in N,N-dimethylformamide (2 mL)/tetrahydrofuran (4 mL), sodium 2- methylpropane-2-thiolate (511 mg) was added, and the mixture was stirred at room temperature for 2 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica

15 gel column chromatography (eluent, ethyl acetate:methanol=100:0->95:5) to give the title compound (159 mg) as a white powder.

¹H-NMR (CDCl₃) δ: 1.30 (9H, s), 3.33 (2H, s), 3.60-3.70 (2H, m), 4.404.50 (2H, m), 6.61 (IH, d, J = 3.3 Hz), 6.85-6.90 (IH, m), 6.95-7.00 (IH, m), 7.00-7.05 (IH, m), 7.07 (IH, d, J = 9.0 Hz), 7.15- 7.25 (2H, m), 7.45-7.55 (IH, m), 7.73 (IH, dd, J = 3.0 Hz, 9.0 Hz), 8.06 (IH, d, J = 2.7 Hz), 8.51 0 (IH₅ S), 8.56 (IH, s).

(ii) Production of 2-(tert-butylsulfonyl)-N-[2-(4-{ [3-cUoro-4-(3-cUorophenoxy)phenyl]amino}- 5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetarnide Using 2-(tert-butylthio)-N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]acetamide (159 mg), OXONE® monopersulfate compound (269 mg) and methanol (5 mL)/water (1.5 mL) and in the same manner as in Example A-3(ii), the title compound (99 mg) was obtained as pale-yellow crystals. 1H-NMR (95%CDCl₃+5%DMSO-d₅) δ: 1.43 (9H, s), 3.50-3.70 (2H, m), 4.00 (2H, s), 4.604.70 (2H, m), 6.60 (IH, d, J = 3.0 Hz), 6.85-6.95 (2H, m), 7.05-7.15 (2H, m), 7.31 (IH, 1, J = 8.1 Hz), 7.60-7.70 (2H, m), 7.92 (IH, s), 8.49 (IH, s), 8.80-8.90 (IH, m), 9.30-9.50 (IH, m). Synthesis Example 287

Production of N-[2-(4-{[3-cWoro-4-(3-cUorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrirnidin- 5-yl)ethyl]-N₅2-dimethyl-2-(methylsulfonyl)propanamide

To a solution of N-[3-chloro4-(3-chlorophenoxy)phenyl]-5-[2-(methylamino)ethyl]-5H- pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (200 mg) and 2-methyl-2- (methylsulfonyi)propanoic acid (100 mg) mN,N-dimethylformamide (5.0 mL) were added triethylamine (0.28 mL) and diethyl cyanophosphonate (0.097 mL) under ice-cooling, and the mixture was stirred at room temperature for 25 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0->-90: 10) and further recrystallized from ethyl acetate/diisopropyl ether to give the title compound (94 mg) as pale-yellow crystals.

¹H-NMR (CDCl₃) δ: 1.85 (6H, s), 2.97 (3H, s), 3.47 (3H, s), 3.70-3.80 (2H, m), 4.40-4.50 (2H₅ m), 6.63 (IH, d, J = 3.6 Hz), 6.85-6.95 (2H, m), 7.00-7.05 (IH, m), 7.06 (IH, d, J = 8.7 Hz), 7.20-7.30 (2H, m), 7.90-8.00 (IH, m), 8.01 (IH, d, J = 2.4 Hz), 8.52 (IH, s), 8.69 (IH, br s). Synthesis Example 288

Production of N-[2-(4-{[3-cMoro-4-(3-methylphenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)emyl]-2-methyl-2-(me11iylsuh^cbnyl)propanamide (i) Production of 5-(2-aminoethyl)-N-[3-chloro-4-(3-methylphenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrirnidin-4-amine dihydrochloride

A mixture of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate (594 mg), 3-chloro-4-(3-methylphenoxy)aniline (467 mg) and isopropyl alcohol (10 mL) was stirred at 80°C for 6 hr. To the reaction mixture was added aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, ethyl acetate:hexane=50:50-»100:0). The objective fractions were concentrated under reduced pressure. To a solution of the residue in methanol (10 mL) was added concentrated hydrochloric acid (3 mL), and the mixture was stirred at room temperature overnight and further at 60⁰C for 3 hr. The reaction mixture was concentrated under reduced pressure. Isopropyl alcohol and toluene were added to the residue, and the mixture was concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure. Isopropyl alcohol 5 and dϋsopropyl ether were added to the residue, and the precipitated solid was collected by filtration to give the title compound (805 mg) as a pale-yellow powder.

¹H-NMR (DMSOd₆) δ: 2.31(3H, s), 3.23-3.37 (2H, m), 5.04 (2H, t, J= 6.2 Hz), 6.72-6.80 (2H, m), 6.83 (IH, m), 6.98 (IH, d, J= 7.5 Hz), 7.18 (IH, d, J= 8.9 Hz), 7.29 (IH, t, J= 7.8 Hz), 7.59 (IH, dd, J= 8.8, 2.5 Hz), 7.87 (IH, d, J= 2.5 Hz), 8.07 (IH, d, J= 3.2 Hz), 8.35 (3H, br s), 8.73 (IH, s), 10.15o (lH, br s).

(ϋ) Production of N-[2-(4-{[3-cUoro4-(3-me1hylphenoxy)phenyl]amino}-5H-ρyrrolo[3^- d]pyrimidm-5-yl)emyl]-2-me1hyl-2-(methylsuhOnyl)propariamide

A mixture of 5-(2-aminoethyl)-N-[3-chloro4-(3-methylphenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (140 mg), 2-methyl-2-(methylsurfonyl)propanoic acid (755 mg), l-e1hyl-3-(3-dimethylaminopropyl)carbodiirnide hydrochloride (86 mg), 1- hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) andN,N-dimethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under o reduced pressure and the obtained residue was subj ected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100— »20:80). The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-dϋsopropyl ether to give the title compound (155 mg) as a white powder. ¹H-NMR(CDCl₃) δ: 1.69 (6H, s), 2.33 (3H, s), 2.93 (3H, s), 3.61-3.74 (2H, m), 4.41-4.51 (2H, m), 6.61 (IH, d, J= 3.3 Hz), 6.75-6.84 (2H, m), 6.89 (IH, d, J= 7.7 Hz), 7.02 (IH, d, J= 8.8 Hz), 7.16- 7.24 (2H₅ m), 7.34 (IH, t, J= 5.8 Hz)₅ 7.80 (IH₅ dd, J= 8.8 Hz₅2.5 Hz), 7.97 (IH₅ d, J= 2.5 Hz)₅ 8.31 (IH, br s), 8.51 (IH₅ S). Synthesis Example 289

Production of N-[2-(4-{[3-cWoro-4-(3-methylphenoxy)phenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)acetamide

A mixture of 5-(2-aminoethyl)-N-[3-cWoro-4-(3-methylρhenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-arnine dihydrochloride (140 mg), methylsulfonylacetic acid (62 mg), l-ethyl-3-(3- dimethylarninopropyl)carbodiirnide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) and N₅N-dmethylformamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→15:85). The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (147 mg) as a white powder. ¹H-NMR (CDCl₃) δ: 2.33 (3H, s), 3.13 (3H, s), 3.63-3.76 (2H, m), 3.70 (2H, s), 4.41-4.53 (2H, m), 6.58 (IH, d, J= 3.3 Hz), 6.75-6.84 (2H, m), 6.90 (IH, d, J= 7.4 Hz), 7.01 (IH, d, J= 8.7 Hz), 7.16- 7.24 (2H, m), 7.55-7.64 (IH, m), 7.69 (IH₃ dd, J= 8.7, 2.7 Hz), 7.89 (IH, d, J= 2.7 Hz), 8.14 (IH, br s), 8.48 (IH, s). Synthesis Example 290

Production of N-[2-(4-{[3-cMoro-4-(3-fluorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-

5-yl)ethyl]-2-methyl-2-(methylsulfonyl)propanamide

(i) Production of 5-(2-aminoethyl)-N-[3-chloro-4-(3-fluorophenoxy)phenyl]-5H-pyrrolo[3 ,2- d]pyrimidin-4-amine diliydrochloride

A mixture of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (594 mg), 3-chloro-4-(3-fiuorophenoxy)aniline (475 mg) and isopropyl alcohol (10 mL) was stirred at 80°C for 6 hr. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, ethyl acetate:hexane=50:50— »100:0). The objective fractions were concentrated under reduced pressure. Methanol (10 mL), tetrahydrofuran (1 mL) and concentrated hydrochloric acid (3 mL) were added to the residue, and the mixture was stirred at room temperature overnight and further stirred at 60⁰C for 3 hr. The reaction mixture was concentrated under reduced pressure. Isopropyl alcohol and toluene were added to the residue, and the mixture was concentrated under reduced pressure. Methanol was added to the residue, and the mixture was concentrated under reduced pressure. Isopropyl alcohol and dϋsopropyl ether were added to the residue and the precipitated solid was 5 collected by filtration to give the title compound (809 mg) as a pale-yellow powder.

¹H-NMR (DMSOd₆) δ: 3.22-3.39 (2H, m), 5.09 (2H, t, J= 6.3 Hz), 6.73-6.82 (2H, m), 6.83-6.92 (IH, m), 6.96-7.05 (IH, m), 7.31 (IH, d, J= 8.9 Hz), 7.39-7.51 (IH, m), 7.66 (IH, dd, J= 2.4 Hz, 8.9 Hz), 7.93 (IH, d, J =2.4 Hz), 8.10 (IH, d, J= 3.2 Hz), 8.42 (3H, br s), 8.74 (IH, s), 10.30 (IH, br s). (ii) Production of N-[2-(4-{[3-chloro-4-(3-fluorophenoxy)phenyl]amino}-5H-pyrrolo[3,2- i o d]pyrimidin-5-yl)ethyl]-2-methyl-2-(methylsuh^conyl)propanarnide

A mixture of 5-(2-aminoethyl)-N-[3-chloro-4-(3-fiuorophenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-amine dihydrochloride (141 mg), 2-methyl-2-(methylsulfonyl)propanoic acid (75 mg), l-ethyl-3-(3-dimethylaminopropyl)carbodiirnide hydrochloride (86 mg), 1- hydroxybenzotriazole (69 mg), triethylamine (0.100 mL) andN,N-dimethylformamide (3 mL) was

15 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 successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0: 100— »20:80). The objective fractions were concentrated under 0 reduced pressure. The residue was crystallized from ethyl acetate-dϋsopropyl ether to give the title compound (161 mg) as a white powder. 1H-NMR (CDCl₃) δ: 1.70 (6H, s), 2.93 (3H, s), 3.63-3.74 (2H, m), 4.424.53 (2H, m), 6.63 (IH, d,

J= 3.3 Hz), 6.64-6.71 (IH, m), 6.74-6.82 (2H, m), 7.09 (IH, d, J= 8.9 Hz), 7.19-7.32 (2H, m), 7.37 (IH, t, J= 5.8 Hz), 7.88 (IH, dd, J= 2.7 Hz, 8.9 Hz), 8.02 (IH, d, J= 2.7 Hz), 8.36 (IH, br s), 8.53

(IH, s).

Synthesis Example 291

5 Production of N-[2-(4-{[3-cMoro-4-(3-fluorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin- 5-yl)ethyl]-2-(methylsulfonyl)acetamide

A mixture of 5-(2-aminoethyl)-N-[3-chloro-4-(3-fluorophenoxy)phenyl]-5H-pyrrolo[3,2- d]pyrirnidin-4-arnine dihydrochloride (141 mg), methylsulfonylacetic acid (62 mg), l-ethyl-3-(3- dimethylarninopropyl)carbodiimide hydrochloride (86 mg), 1-hydroxybenzotriazole (69 mg), o triethylamine (0.100 mL) and HN-dimethyUbrmamide (3 mL) was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to basic silica gel column chromatography (eluent, methanol:ethyl acetate=0:100-»15:85). The objective fractions were concentrated under reduced pressure. The residue was crystallized from ethyl acetate-dϋsopropyl ether to give the title compound (146 mg) as a white powder. ¹H-NMR (CDCl₃) δ: 3.14 (3H, s), 3.64-3.76 (2H, m), 3.98 (2H, s), 4.43-4.54 (2H, m), 6.59 (IH, d, J= 3.3 Hz), 6.63-6.70 (IH, m), 6.73-6.82 (2H, m), 7.08 (IH, d, J= 8.9 Hz), 7.18-7.31 (2H, m), 7.57- 7.65 (IH, m), 7.75 (IH, dd, J= 2.5 Hz, 8.9 Hz), 7.93 (IH, d, J= 2.5 Hz), 8.19 (IH, br s), 8.49 (IH, s). Synthesis Example 292

Production of N-[2-(4-{[4-(3-cMorophenoxy)-3-methylpheny d]pyrimidin-5-yl)etiiyl]-2-me1hyl-2-(methylsulfonyl)propanami

(i) Production of tert-butyl [2-(4-{[4-(3-cUorophenoxy)-3-metihLylphenyl]arnino}-5H-pyrrolo[3,2- d]pyrirnidin-5-yl)ethyl]carbamate

A solution of tert-butyl [2-(4-cMoro-5H-pyπ"olo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate (1.0 g) and 3-methyl-4-[3-chlorophenoxy]aniline (1.18 g) in isopropyl alcohol (10 mL) was stirred at 80°C for 12 hr. Aqueous sodium bicarbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=8:2— >ethyl acetate) to give the title compound (1.7 g) as colorless crystals. 1H-NMR (CDCl₃) δ: 1.47 (9H, s), 2.20 (3H, s), 3.48 (2H, m), 4.45 (2H,m), 5.16 (IH, m), 6.57 (IH, d, J= 3 Hz), 6.80-7.00 (4H, m), 7.10-7.30 (2H, m), 7.68 (2H, m), 8.40 (IH, br s), 8.49 (IH, s). (ii) Production of 5-(2-aminoethyl)-N-[4-(3-chlorophenoxy)-3-methylphenyl]-5H-pyrrolo[3,2- d]pyrimidin-4-arnine dihydrochloride

A mixture oftert-butyl [2-(4-{[4-(3-chlorophenoxy)-3-methylphenyl]arnino}-5H- pyrrolo[3,2-d]pyrirnidin-5-yl)ethyl]carbamate (1.6 g), 2N hydrochloric acid (23 mL) and 5 tetrahydrofuran (46 mL) was stirred at 6O⁰C for 20 hr. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. The resulting crystals were collected by filtration. The crystals were washed with isopropyl ether to give the title compound

(1.35 g) as a pale-yellow powder.

¹H-NMR (DMSOd₆) δ: 2.19 (3H, s), 3.30 (2H, m), 5.04 (2H, m), 6.72 (IH, d, J= 3 Hz), 6.80-7.00o (2H, m), 7.08 (IH, d, J= 9 Hz), 7.16 (IH, dd, J= 2 Hz, 8 Hz), 7.30-7.50 (2H, m), 7.54 (IH, m), 8.06

(IH, m), 8.40 (3H, br s), 8.68 (IH, s), 10.00 (IH, br s).

(ϋi) Production of N-[2-(4- { [4-(3 -chlorophenoxy)-3 -methylphenyl]arnino} -5H-pyrrolo[3 ,2- dJpyrirrήdm-S-y^emylJ^-methyl^-^ethylsutfony^propariamide

A mixtιιre of5-(2-aminoethyl)-N-[4-(3-chlorophenoxy)-3-methylphenyl]-5H-pyrrolo[3,2- 5 d]pyrimidin-4-amine dihydrochloride (167 mg), 2-methyl-2-(methylsurfonyl)propanoic acid (89 mg), l-e1hyl-3-(3-dimemylaminopropyl)carbodiimide hydrochloride (103 mg), 1- hydroxybenzotriazole (72.5 mg), triethylamine (0.15 mL) andN,N-dimemylformamide (6.9 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and o saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=85:15) to give the title compound (179 mg) as colorless crystals. ¹H-NMR (DMSOd₆) δ: 1.42 (6H, s), 2.14 (3H, s), 2.96 (3H, s), 3.47 (2H, q, J= 6 Hz), 4.56 (2H, t, J= 6 Hz), 6.45 (IH, d, J= 3 Hz), 6.80-6.90 (2H, m), 7.02 (IH, d, J= 9 Hz), 7.11 (IH, dd, J= 1 Hz, 8 Hz), 7.37 (IH, t, J= 8 Hz), 7.52 (IH, d, J= 3 Hz), 7.58 (2H, m), 8.20 (IH, t, J= 6 Hz), 8.28 (IH, s),

8.49 (lH, brs). Synthesis Example 293

Production of N-[2-(4-{[4-(3-cUorophenoxy)-3-methylphenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)efhyl]-2-(methylsulfonyl)acetamide

A mixture of 5-(2-amkoe1%l)-N-[4-(3-chlorophenoxy)-3-methylphenyl]-5H-pyrrolo[3,2- d]pyrirnidin-4-amine dihydrochloride (167 mg), methylsulfonylacetic acid (74 mg), l-ethyl-3-(3- dimethylammopropyl)carbodiimide hydrochloride (103 mg), 1-hydroxybenzotriazole (72.5 mg), triethylamine (0.15 mL) and N^Sf-dimethylformamide (6.9 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate— Methyl acetate:methanol=85:15) to give the title compound (177 mg) as colorless crystals. ¹H-NMR (DMSO-de) δ: 2.13 (3H, s), 3.09 (3H, s), 3.45 (2H, q, J= 6 Hz), 4.05 (2H, s), 4.55 (2H, t, J= 6 Hz), 6.46 (IH, d, J= 3 Hz), 6.80-6.95 (2H, m), 7.00 (IH, d, J= 9 Hz), 7.11 (IH, m), 7.37 (IH, t,

J= 8 Hz), 7.56 (3H, m), 8.28 (IH, s), 8.52 (IH, br s), 8.66 (IH, m). Synthesis Example 294

Production of N-[2-(4-{[4-(3-cMorophenoxy)-3-me1hylphenyl]amino}-5H-pyrrolo[3,2- d]pyrimidin-5-yl)ethyl]-2-(methylsulfonyl)propanamide

A mixture of 5-(2-aminoethyl)-N-[4-(3-chlorophenoxy)-3-methylphenyl]-5H-pyrrolo[3,2- d]pyrirnidin-4-arnine dihydrochloride (192 mg), 2-chloropropanoic acid (0.057 mL), l-ethyl-3-(3- dimethylarninopropyl)carbodiimide hydrochloride (126 mg), 1-hydroxybenzotriazole (90 mg), triethylamine (0.29 mL) andN,N-dimethylformamide (4 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate-»ethyl acetate:methanol^:=90:10), and the fraction containing 2-chloro-N-[2-(4-{[4-(3-chlorophenoxy)-3- me1hylphenyl]amMo}-5H-pyrrolo[3,2-d]pyrirrύα%-5-yl)e1hyl]propanamide was concentrated under reduced pressure. The residue was dissolved in N,N-climethylformamide (4 mL) and pyridine (0.4 mL), sodium methanesulfinic acid (420 mg) was added and the mixture was stirred at 70°C for 2 days. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent,

ethyl acetate-»ethyl acetate:methanol=85:15) to give the title compound (116 mg) as colorless crystals.

¹H-NMR (DMSOd₆) δ: 1.36 (3H₅ d, J= 7 Hz), 2.13 (3H₅ s), 2.95 (3H₅ s), 3.50 (2H₅ m), 3.82 (IH₅ m), 4.53 (2H, m), 6.46 (IH, d, J= 3 Hz)₅ 6.80-6.90 (2H₅ m), 7.01 (IH₅ d₅ J= 9 Hz)₅7.10 (IH₅ d, J= 8

Hz)₅ 7.37 (IH, t, J= 8 Hz)₅ 7.57 (3H, m), 8.28 (IH₅ s), 8.49 (IH₅ br s), 8.59 (IH₅1, J= 6 Hz). Synthesis Example 295

Production of N-[2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl]arnino}-5H-pyrrolo[3,2-d]pyrimidin- S-y^ethylJ^-methyl^-^emylsutfony^propanamidep-toluenesulfonate

Ethyl acetate (200 mL) and ethanol (70 mL) were added to N-[2-(4-{[3-chloro-4-(3- cMorophenoxy)phenyl]arriino}-5H-pyrrolo[3₅2-d]pyrimidin-5-yl)ethyl]-2-methyl-2-

(methylsulfonyl)propanamide (9.0 g), the mixture was dissolved by heating at 65°C₅ and p- toluenesulfonic acid monohydrate (3.04 g) was added. The mixture was stood at room temperature under light shielding for 23 hr and the resulting crystals were collected by filtration. The crystals were washed with a small amount of ethyl acetate and diisopropyl ether to give the title compound (11.5 g) as colorless crystals. ¹H-NMR (DMSO-dg) δ: 1.40 (6H₅ s), 2.28 (3H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m), 6.65 (IH, d, J = 3.0 Hz), 6.90-7.00 (IH, m), 7.00-7.05 (IH, m), 7.10 (2H, d, J = 7.8 Hz), 7.20-

7.25 (IH, m), 7.35 (IH, d, J = 9.0 Hz), 7.40-7.50 (3H, m), 7.60-7.70 (IH, in), 7.89 (IH, d, J = 3.0

Hz), 7.91 (IH, d, J = 1.8 Hz), 8.15-8.25 (IH, m), 8.74 (IH, s), 9.80 (IH, br s).

elemental analysis for C₃₂H₃₃Cl₂N₅O₇S₂

Calculated: C,52.32; H,4.53; N.9.53.

Found : Q52.35; H,4.54; N.9.49.

mp 217-218°C. Synthesis Example 296

Production of N-[2-(4-{[3-cMoro-4-(3-cMorophenoxy)phenyl]amino}-5H-pyrrolo[3,2-d]pyrimidin-

5-yl)ethyl]-2-methyl-2-(methylsulfonyl)pro^

Acetone (20 mL) was added to N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-

5H-pyrrolo[3,2-d]pyriinidin-5-yl)e1hyl]-2-methyl-2-(me1hylsulfonyl)propa^ (500 mg), and

the mixture was dissolved by heating at 40⁰C, and p-toluenesulfonic acid monohydrate (168 mg) was added. The mixture was stood at room temperature under light shielding for 4 days, and

concentrated under reduced pressure. Ethyl acetate (12 mL) and ethanol (4 mL) were added to the

residue, and the mixture was dissolved by heating at 60°C. The mixture was stood at room temperarure for 17 hr under light shielding, and resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to give the title compound (543 mg) as colorless crystals.

¹H-NMR (DMSOd₆) δ: 1.40 (6H₅ s), 2.29 (3H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m), 6.65 (IH, d, J = 3.0 Hz), 6.90-7.00 (IH₅ m), 7.00-7.05 (IH, m), 7.10 (2H, d, J = 7.8 Hz), 7.20-

7.25 (IH, m), 7.35 (IH, d, J = 9.0 Hz), 7.40-7.50 (3H₅ m), 7.67 (IH₅ dd, J = 2.4 Hz, 9.0 Hz)₅7.88

(IH₅ d, J = 3.0 Hz)₅7.92 (IH, d, J = 2.4 Hz)₅ 8.15-8.25 (IH₅ m), 8.73 (IH₅ s), 9.76 (IH₅ br s).

elemental analysis for C₃₂H₃₃Cl₂N₅O₇S₂- 1.0H₂O Calculated: C.51.06; H₅4.69; N,9.30.

Found : Q50.49; H₅4.52; N₅9.23.

mp 216-217°C.

Synthesis Example 297

Production of N-[2-(4-{[3-cMoro-4-(3-cUorophenoxy)phenyl]amrno}-5H-pyrrolo[3,2-d]pyrimidin-

5-yl)e1hyl]-2-me1hyl-2-(methylsulfonyl)prop

ToN-[2-(4-{[3-cMoro4-(3-cMorophenoxy)phenyl]amMo}-5H-pyrrolo[3₅2-d]pyrirrύdin-5-

y^ethyy^-methyl^-^ethylsurfony^propanamide (400 mg) were added ethyl acetate (12 mL) and

ethanol (4 mL), and the mixture was dissolved by heating at 60°C, and benzenesulfonic acid monohydrate (132 mg) was added. The mixture was stood at room temperature for 17 hr under

light shielding and concentrated under reduced pressure, and ethyl acetate (10 mL) was added to the

residue. The mixture was stood at room temperature for 17 hr under light shielding, and resulting crystals were collected by filtration. The crystals were washed with dϋsopropyl ether to give the title compound (447 mg) as colorless crystals.

¹H-NMR (DMSOd₆) δ: 1.41 (6H, s), 2.93 (3H, s), 3.50-3.60 (2H, m), 4.65-4.75 (2H, m), 6.65 (IH, d, J - 3.0 Hz), 6.95-7.00 (IH, m), 7.00-7.05 (IH, m), 7.20-7.25 (IH, m), 7.25-7.35 (3H, m), 7.35 5 (IH, d, J - 8.4 Hz), 7.45 (IH, t, J = 8.4 Hz), 7.55-7.65 (2H, m), 7.67 (IH, dd, J = 2.4, 8.7 Hz), 7.88 (IH, d, J = 3.0 Hz), 7.93 (IH, d, J = 2.4 Hz), 8.20-8.25 (IH, m), 8.73 (IH, s), 9.74 (IH, br s). elemental analysis for C₃₁H₃₁Cl₂N₅O₇S₂" 1.0H₂O Calculated: C,50.41; H,4.50; N,9.48. Found : C,50.53; H,4.43; N,9.48. o mp l42-144°C.

Synthesis Example 298

Production of N-[2-(4-{[3-crύoro-4-(3-cUorophenoxy)phenyl]ammo}-5H-pyrrolo[3,2-d]pyrirnidin- 5-yl)ethyl]-2-me11iyl-2-(me1hylsulfonyl)propanamide hydrochloride 5 Acetone (20 mL) was added to N-[2-(4-{[3-chloro-4-(3-chlorophenoxy)phenyl]amino}-

5H-pyrrolo[3,2-d]pyrirrndin-5-yl)elhyl]-2-methyl-2-(me1hylsulfonyl)proparian^ (400 mg), and the mixture was dissolved by heating at 40°C. 4N Hydrogen chloride/ethyl acetate solution (0.196 mL) was added. The mixture was stood at room temperature for 4 days under light shielding, and resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether to o give the title compound (401 mg) as pale-yellow crystals. ¹H-NMR (DMSOd₆) δ: 1.40 (6H, s), 2.93 (3H₅ s), 3.50-3.65 (2H₅ m), 4.4.70-4.80 (2H₅ m), 6.65 (IH, d, J = 3.0 Hz)₅ 6.90-7.00 (IH₅ m), 7.00-7.05 (IH₅ m), 7.20-7.25 (IH₅ m), 7.35 (IH₅ d, J = 8.7

Hz)₅ 7.45 (IH₅ t, J = 8.1 Hz)₅7.68 (IH₅ dd, J = 2.4 Hz₅ 8.7 Hz), 7.89 (IH, d, J = 3.0 Hz), 7.94 (IH₅ d,

J = 2.4 Hz)₅ 8.20-8.30 (IH, m), 8.73 (IH₅ s), 9.89 (IH₅ br s).

elemental analysis for C₂₅H₂₆Cl₃NsO₄S

Calculated: Q50.13; H₅4.38; N₅11.69.

Found : C,49.70; H.4.41; N₅11.48.

mp 194-195°C. Synthesis Example 299

Production of N-(2-(4-((3-chloro-4-(4-fluoro-3-me1hylphenoxy)phenyl)aniino)-5H-pyrrolo[3,2- d]pyriirύdin-5-yl)ethyl)-2-(me1hylsulfonyl)ace1arnide

A mixture of tert-butyl [2-(4-cMoro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (1.00

g), 3-cUoro-4-(4-fluoro-3-methylphenoxy)aniline (1.51 g) and isopropyl alcohol (10 mL) was

stirred at 80°C for 12 hr. Aqueous sodium bicarbonate was added to the reaction mixture under ice- cooling and the mixture was extracted with ethyl acetate. The organic layer was washed with brine

and dried over anhydrous magnesium sulfate. The residue was separated and purified by silica gel

column chromatography (eluent, ethyl acetate:hexane=60:40— »100:0) to give a crude product (1.52 g). The obtained crude product (150 mg) was dissolved in tetrahydrofuran (22.2 mL). 4N Hydrogen chloride/ethyl acetate solution (11.5 mL) was added, and the mixture was stirred at 7O⁰C for 20 hr. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. Dϋsopropyl ether was added, and the precipitated powder was collected by filtration. A mixture of the obtained powder, methylsulfonylacetic acid (74 mg), l-ethyl-3-(3- 5 climethylaminopropytycarbocliirnide hydrochloride (103 mg), 1-hydroxybenzotriazole (72 mg), triethylamine (0.15 mL) and N^Sf-dimethyrformamide (7.0 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and i o purified by basic silica gel column chromatography (eluent, ethyl acetate— >ethyl acetate:methanol=90: 10) and crystallized from diisopropyl ether to give the title compound (116 mg) as colorless crystals.

¹H-NMR (DMSOd₆) δ: 2.22 (3H, s), 3.10 (3H, s), 3.46 (2H, q, J = 6.0 Hz), 4.04 (2H, s), 4.55 (ZH, t, J = 6.0 Hz), 6.49-7.17 (5H, m), 7.61-7.93 (3H, m), 8.33 (IH, s), 8.65-8.66 (2H, m). s FORMULATION EXAMPLES

Formulation Example 1 (amount per tablet)

( 1 ) Compound obtained in Synthesis Example 39 10.0 mg

(2) Lactose 60.0 mg

(3) Com starch 35.0 mg 0 (4) Gelatin 3.0 mg

(5) Magnesium stearate 2.0 mg

A mixture of 10.0 mg of the compound obtained in Synthesis Example 39, 60.0 mg of lactose and 35.0 mg of corn starch is granulated through a 1 mm-mesh sieve using 0.03 ml of a 10% by weight aqueous solution of gelatin (3.0 mg of gelatin), after which the granules are dried at 40°C and filtered again. The granules obtained are mixed with 2.0 mg of magnesium stearate and compressed. The core tablets obtained are coated with a sugar coat comprising a suspension of sucrose, titanium dioxide, talc and gum arabic and polished with beeswax to yield sugar-coated tablets.

Formulation Example 2 (dose per tablet)

(1) Compound obtained in Synthesis Example 39 10.0 mg

(2) Lactose 70.0 mg

(3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg

(5) Magnesium stearate 3.0 mg

10.0 mg of the compound obtained in Synthesis Example 39 and 3.0 mg of magnesium stearate are granulated using 0.07 ml of an aqueous solution of soluble starch (7.0 mg of soluble starch), after which these granules are dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. This mixture is compressed to yield tablets.

SUPPLEMENTAL EXPERIMENTAL EXAMPLES

Supplemental Experimental Example IA Cloning of human HER2 gene and preparation of recombinant baculovirus

Human HER2 gene was cloned by RT-PCR using total RNA prepared from MCF7 cells as a template. The primer used for RT-PCR was prepared from nucleotide sequence (Genbank

Accession Ml 1730) information of HER2 gene by adding a nucleotide sequence encoding flag peptide and a restriction enzyme recognition sequence to a nucleotide sequence (2176-3918 of Genbank Accession Ml 1730) encoding the HER2 intracellular domain region, so that the protein contains an N-terminal Flag tag. The primer nucleotide sequence is shown below. HER2-U:5'-

AATTAAGTCGACATGGACTACAAAGACGATGACGACAAGCGACGGCAGCAGAAGA 5 TCCGGAAGTAC-3 '(SEQ ID NO: 1) and

HER2-L:

5'-AATTAAGCATGCTCACACTGGCACGTCCAGACCCAGGTACTC-3'(SEQ ID NO:2) The RT reaction was conducted using Superscript First-Strand Synthesis System for RT- i o PCR (Invitrogen) and the PCR reaction was conducted using a KOD-plus kit (TOYOBO). The obtained PCR product was electrophoresed on agarose gel (1%), the DNA fragment amplified by PCR was recovered from the gel, and then digested with restriction enzymes Sal I and Sph I. The DNA treated with the restriction enzymes was electrophoresed on agarose gel (1%), and the obtained DNA fragment was recovered and ligated to plasmid pF ASTB ACl (Invitrogen) digested

15 with restriction enzymes Sal I and Sph I to give expression plasmid pFB-HER2. The nucleotide sequence of the insertion fragment was confirmed and found to be identical with the nucleotide sequence (2176-3918 of Genbank Accession Ml 1730) of HER2 intracellular domain. Furthermore, using BAC-TO-BAC Baculovirus Expression System (Invitrogen), recombinant baculovirus BAC- HER2 was prepared. 0 Supplemental Experimental Example IB Preparation of HER2 intracellular domain protein

SF-21 cells were sown at 1 x 10⁶ cells/mL to Sf-900H SFM medium (1 L, Invitrogen) containing 10% fetal bovine serum (trace), 50 mg/L gentamicin (Invitrogen) and 0.1% Pluronic F-

68 (Invitrogen), and shaking culture was performed using a 2 L volume Erlenmeyer flask at 27°C, 100 rpm. After culturing for 24 hrs, recombinant baculovirus BAC-HER2 (13.4 mL) was added, and the mixture was further cultured for 3 days. The culture medium was centrifuged at 2,000 rpm for 5 min. to give virus-infected cells. The infected cells were washed with a phosphate buffered saline (Tnvitrogen), centrifuged under the same conditions, and the cells were preserved at -80⁰C. 5 The cryopreserved cells were thawed in ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH 7.4) containing 20% glycerol, 0.15 MNaCl) supplemented with Complete Protease Inhibitor (Boehringer), and ruptured 3 times with a Polytron homogenizer (Kinematica) at 20,000 rpm for 30 sec. The rupture medium was clarified by centrifugation at 40,000 rpm for 30 min. and filtered with a 0.45 μm filter. The filtrate was passed through a column packed with Anti-FLAG M2 Affinity i o Gel (4 mL, Sigma) at a flow rate of about 0.5 mL/min. The column was washed with buffer A, and eluted with buffer A containing 100 μg/mL of FLAG peptide. The eluate was concentrated with Vivaspin 20 (Vivascience) having a molecular weight cut off of 30K. The concentrate was purified by gel filtration using Hi Load Superdex 200pg 16/60 (Amersham Bioscience) equilibrated with buffer A. The fractions containing HER2 intracellular domain were collected, glycerol was added

25 to the final concentration of 50% and cryopreserved at -80°C.

Supplemental Experimental Example 1C Determination of HER2 kinase inhibitory activity

A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted with a buffer for kinase reaction (50 mM Tris-HCl (pH7.5), 5 mM MgCl₂, 5 mM MnCl₂, 2 mM dithiothreitol, 0.01% Tween-20). To this compound solution (10 μL) was added a buffer for kinase reaction (20 μL) 0 containing 5 μg/mL of HER2 intracellular domain obtained in Supplemental Experimental

Example IB and 12.5 μg/mL of polypeptide substrate poly-Glu:Tyr (4: 1) (Sigma). To the obtained mixture was added 20 μL of ATP solution (1.25 μM ATP, 0.05 μCi [γ-³²P]ATP), the mixture was allowed to react at 25°C for 10 min. and the reaction was quenched with 50 μL of 20% TCA solution. The reaction solution was allowed to stand at 4°C for 20 min., and the acid insoluble

fraction was transferred to GF/C filter (PerkinElmer) using cell harvester (PerkinElmer) and washed

with 250 mM phosphoric acid solution. After washing, the plate was dried at 45°C for 60 min., and

35 μL of MicroScinti 0 (PerkinElmer) was added. The radioactivity was measured using TopCount

5 (PerkinElmer). HER2 kinase inhibitory rate (%) of the test compound was calculated by the

following formula:

Inhibitory rate (%)=(1 -(count of test compound - blank)÷(control - blank))xlOO

The count of the solution reacted without addition of the compound was used as a "control",

and the count of the solution without the compound and HER2 intracellular domain was used as a

i o "blank". The results of the inhibitory rate of the compounds are shown in Table 1.

From the foregoing, it was shown that the compounds in this invention strongly inhibited

the activity of HER2 kinase.

Table 1

Synthesis Example No. (compound No.) Inhibitory rate (%) at 1.0 μM ' Ϊ3 949

38 95.9

39 96.1 158 87.0

190 95.9

191 100

5 Supplemental Experimental Example 2A Cloning of human EGF receptor gene and preparation

of recombinant baculovirus

Human EGF receptor gene was cloned by RT-PCR using total RNA prepared from A431

cells as a template. The primer for RT-PCR was prepared from nucleotide sequence (Genbank Accession XM_167493) information of EGF receptor gene by adding a nucleotide sequence encoding flag peptide and a restriction enzyme recognition sequence to a nucleotide sequence (2182-3810 of Genbank Accession XM_167493) encoding EGF receptor intracellular domain region, so that the protein contains an N-terminal Flag tag. The primer nucleotide sequence is shown below. EGFR-U: 5'-

AATTAAGTCGACATGGACTACAAAGACGATGACGACCGAAGGCGCCACATCGTTC GGAAGCGCACG-3'(SEQ ID NO:3) and EGFR-L:

5'-AATTAAGCATGCTCATGCTCCAATAAATTCACTGCTTTGTGG-SXSEQ ID NO:4)

The RT reaction was conducted using Superscript First-Strand Synthesis System for RT- PCR (Tnvirrogen) and the PCR reaction was conducted using a KOD-plus kit (TOYOBO). The obtained PCR product was electrophoresed on agarose gel (1%), the DNA fragment amplified by PCR was recovered from the gel, and then digested with restriction enzymes Sal I and Sph I. The DNA treated with the restriction enzymes was electrophoresed on agarose gel (1%), and the obtained DNA fragment was recovered and ligated to plasmid pFASTBACl (Thvitrogen) digested with restriction enzymes Sal I and Sph I to give expression plasmid pFB-EGFR The nucleotide sequence of insertion fragment was confirmed and found to be identical with the nucleotide sequence (2182-3810 of Genbank Accession XMJ 67493) of EGFR intracellular domain.

Furthermore, using BAC-TO-BAC Baculovirus Expression System (Invitrogen), virus stock BAC- EGFR of recombinant baculovirus was prepared. Supplemental Experimental Example 2B Preparation of EGF receptor intracellular domain protein

SF-21 cells were sown at 1 x 10⁶ cells/mL to Sf-900π SFM medium (1 L, rnvitrogen) containing 10% fetal bovine serum (trace), 50 mg/L gentamicin (fnvitrogen) and 0.1% Pluronic F- 5 68 (rnvitrogen), and shaking culture was performed using a 2 L volume Erlenmeyer flask at 27⁰C, 100 rpm. After culturing for 24 hrs, recombinant baculovirus BAC-EGFR (13.4 mL) was added, and the mixture was further cultured for 3 days. The culture medium was centrifuged at 2,000 rpm for 5 min. to give virus-infected cells. The infected cells were washed with a phosphate buffered saline (Invitrogen), centrifuged under the same conditions, and the cells were preserved at -80⁰C. i o The cryopreserved cells were thawed in ice, suspended in buffer A (50 mM Tris buffer (30 mL, pH7.4) containing 20% glycerol, 0.15 MNaCl) supplemented with Complete Protease Inhibitor (Boehringer), and ruptured 3 times with a Polytron homogenizer (BCinematica) at 20,000 rpm for 30 sec. The ruptured medium was clarified by centrifugation at 40,000 rpm for 30 min. and filtered with a 0.45 μm filter. The filtrate was passed through a column packed with Anti-FLAG M2

15 Affinity Gel (4 mL, Sigma) at a flow rate of about 0.5 mL/min. The column was washed with buffer A, and eluted with buffer A containing 100 μg/mL of FLAG peptide. The eluate was concentrated with Vivaspin 20 (Vivascience) having a molecular weight cut off of 30K. The buffer of this concentrate was exchanged using NAP™ 25 column (Amersham Bioscience) equilibrated with buffer A. The fractions containing EGF receptor intracellular domain protein were collected, 0 glycerol was added to the final concentration of 50% and cryopreserved at -80⁰C.

Supplemental Experimental Example 2C Determination of EGF receptor kinase inhibitory activity A test compound dissolved in dimethyl sulfoxide (DMSO) was diluted with a buffer (50 mM Tris-HCl (pH 7.5), 5 mM MgCl₂, 5 mM MnCl₂, 2 mM dithiothreitol, 0.01% Tween-20). To this compound solution (5 μL) was added a buffer (10 μL) containing 250 ng/mL of EGF receptor intracellular domain protein and 250 ng/mL of biotin labeled polypeptide biotinyl-poly-Glu:Tyr 5 (4:1) (CIS bio International). To the obtained mixture was added abuffer (10 μL) containing ATP (5 μM), the mixture was allowed to react at 25°C for 10 min. and the reaction was quenched with 25 μL of a stop solution (100 mM EDTA disodium salt, 62.5 mM HEPES buffer (pH 7.4), 250 mM NaCl, 0.1% bovine serum albumin, 10 μg/mL AlphaScreen assay streptavidin donor beads (Streptavidin Donor beads: PerkinElmer), 10 μg/mL AlphaScreen assay anti-phosphotyrosine i o recognition antibody PY- 100 binding acceptor beads (Anti-phosphotyrosine (P-Tyr- 100) Acceptor beads: PerkinElmer)). The reaction solution was allowed to stand at 25⁰C for 16 hrs, and the cells were counted using a plate reader Fusion™ (PerkinElmer). The kinase inhibitory rate (%) of the test compound was calculated by the following formula:

Inhibitory rate (%)=(1 -(count of test compound - blank)÷(control - blank))xlOO is The count of the solution reacted without addition of the compound was used as a "control", and the count of the solution without the compound and ATP was used as a "blank". The results of the inhibitory rate of the compounds are shown in Table 2.

From the foregoing, it was shown that the compounds in this invention strongly inhibited the activity of EGF receptor kinase. 0 Table 2

Synthesis Example No. (compound No.) Inhibitory rate (%) at 1.0 μM

22 9&5

41 98.9

92 98.0

138 99.0

147 96.0

160 97.0

Supplemental Experimental Example 3 Inhibitory action on breast cancer cell BT-474

proliferation in vitro

5 A suspension of human breast cancer cell BT-474 (100 μl (6,000 cells)) were sown to a

96-well microplate and cultured in an incubator (37°C, 5% carbon dioxide). On the following day,

100 μl of a solution of each test compound, which was previously diluted 2-fold, was added, and the

cells were cultured for 5 days. After the culture medium containing the test compound was removed,

the cells were washed and fixed with 50% trichloroacetic acid, after which a 0.4% (w/v) SRB

i o solution (dissolved in 1% acetic acid) was added to fix and stain the cell protein (Skehan et al.,

Journal of the National Cancer Institute, Vol. 82, pp. 1107-1112, 1990). After washing with a 1%

acetic acid solution, 100 μl of an extract (10 mM Tris solution) was added to extract the pigment,

and absorbance was measured at an absorption wavelength of 550 nm to quantify the amount of

cells as protein content Taking as 100% the protein content for the control group, which received no

15 test compound solution, the ratio of the residual protein content for each treatment group was

determined, and the compound concentration required to achieve 50% suppression of the residual

cell content relative to the control (IC₅₀ value) was calculated. The results are shown in Table 3. Table 3

Supplemental Example No. IC₅o(nM) (compound No.)

82 <100

92 <100

169 <100

176 <100

This application is based on a US provisional patent application No. 61/100,624, the contents of which are incorporated in full herein by this reference.

Claims

1. A method for protecting heart of a mammal in need thereof, the method comprising administering to the mammal an effective amount of at least one of Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by the formula:

X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and

Y is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-

(Q₄ alkylene)-,

1 9 0 3

are excluded.

2. The method for protecting heart of a mammal in need thereof according to claim 1, which protects the heart from damages caused by a cardiotoxic material, free radicals, oxidation, β-oxidation of fatty acid, chemotherapy, radiation to radio active materials, TNFα, other cytokines, cardiomyopathy, ischemia, hypoxia, obesity, lipidemia, low-density lipoprotein (LDL), other lipid accumulation, glucose deprivation, starvation, heart transplant, statins, and HMG-CoA reductase inhibitors.

3. The method for protecting heart of a mammal in need thereof according to claim 1 , which protects the heart from damages caused by the cardiotoxic material.

4. The method for protecting heart of a mammal in need thereof according to claim 1 , which protects the heart from cardiomyopathy.

5. The method for protecting heart of a mammal in need thereof according to claim 1 , which protects the heart from ischemic injury.

6. The method for protecting heart of a mammal in need thereof according to claim 1 , wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

R²*¹ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R ^a and R , or R and R ^a are optionally bonded to form an optionally substituted ring structure,

R^3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,

B^ais an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

7. A method for protecting heart of a mammal, the method comprising administering to the mammal an effective amount of N-{2-[4-({3-chloro-4-[3- (ttifluoromethyl)phenoxy]phenyl}amin^^ hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof.

8. A pharmaceutical composition for protecting heart of a mammal in need thereof comprising at least one of Compound (T), a salt thereof, or a prodrug thereof in a therapeutically effective amount wherein the Compound (T) is represented by the formula:

wherein W is C(R¹) or N₅

A is an optionally substituted aryl group or an optionally substituted heteroaryl group,o X¹ is -NR³- Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y¹ is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-5 (CM alkylene)-,

R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or R¹ and R², or R² and R³ are optionally bonded to form an optionally substituted ring o structure, provided that compounds represented by formulas

are excluded.

9. The pharmaceutical composition for protecting heart of a mammal in need thereof according to claim 8, wherein the at least one of Compound (J), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the

Compound (Ta) is represented by a formula:

R^ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R^laand R²⁸, or R^ and R^3a are optionally bonded to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and C^a is an optionally substituted C_6-18 aiyl group, or a salt thereof.

10. A pharmaceutical composition for protecting heart of a mammal in need thereof comprising N-{2-[4-({3-cWoro-4-[3-(trύluorome1hyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-

5 d]pyrimidm-5-yl]ethyl}-3-hydroxy-3-methylbu1anamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount.

11. A use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for protecting heart of a mammal in need thereof, wherein the o Compound (T) is represented by the formula:

wherein W is C(R¹) or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X¹ is

-O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

R is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y is a single bond or an optionally substituted CM atkylene or an optionally substituted -O- (CM alkylene)-, R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R and R , or R² and R are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas

are excluded.

12. The use of at least one of Compound (T), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for protecting heart of a mammal in need thereof according to claim 11 , wherein the at least one of Compound (T), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

R >2a is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R^la and R²*¹, or R²*¹ and R^3a are optionally bonded to form an optionally substituted ring structure,

R^3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R^3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

13. A use of N-{2-[4-({3-chloro-4-[3-(trifluoromethyl) phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimid1n-5-yl]ethyl}-3-hydroxy-3-methylbutanarnide, a saltthereof, or a prodrug thereof for preparing a pharmaceutical composition for protecting heart of a mammal in need thereof.

14. A method for activating an AMP-activated protein kinase, the method comprising administering to a mammal in need thereof an effective amount of at least one of

Compound (T), a salt thereof, or a prodrug thereof, wherein the Compound (T) is represented by a formula:

wherein W is C(R¹) or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

Y¹ is a single bond or an optionally substituted C^ alkylene or an optionally substituted -0-

(Q-₄ alkylene)-,

R is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R² is a hydrogen atom or an optionally substituted group bonded via a carbon atom or a sulfur atom, or

are excluded.

15. The method for activating an AMP-activated protein kinase according to claim 14, wherein the at least one of Compound (I), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ta) is represented by a formula:

R²⁸ is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R^la and R²⁸, or R^ and R^3a are optionally bonded to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

16. A method for activating an AMP-activated protein kinase, 1he method comprising administering to a mammal in need thereof an effective amount of N-{2-[4-({3-chloro-4-[3- (1rifluoromethyl)phenoxy]phenyl}ammo)-5H-pyrrolo[3,2-d]pyrirrdcϋn-5-yl]ethyl}-3- hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof.

17. A pharmaceutical composition for activating an AMP-activated protein kinase comprising at least one of Compound (T), a salt thereof, or a prodrug thereof in a therapeutically effective amount, wherein the Compound (T) is represented by a formula:

5 wherein W is C(R¹) or N,

X¹ is -NJ^-Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R³ is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or

(CM alkylene)-,

R¹ is a hydrogen atom or an optionally substituted group bonded via a carbon atom, a nitrogen atom or an oxygen atom, and R is a hydrogen atom or an optionally substituted 15 group bonded via a carbon atom or a sulfur atom, or

are excluded.

18. The pharmaceutical composition for activating an AMP-activated protein kinase according to claim 17, wherein the at least one of Compound (T), a salt thereof, or aprodrug thereof is at least one of Compound (Ta), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

R^2*1 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R^la and R²⁸, or R²*¹ and R ^a are optionally bonded to form an optionally substituted ring structure,

R^3a is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R3a is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

19. A pharmaceutical composition for activating an AMP-activated protein kinase comprising N-{2-[4-({3-cMoro-4-[3-(tiifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof in a therapeutically effective amount.

20. A use of at least one of Compound (J), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for activating an AMP-activated protein kinase, wherein the

Compound (T) is represented by a formula:

wherein W is C(R¹) or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X¹ is -NR^Y¹-, -O-, -S-, -SO-, -SO₂- or -CHR³- wherein R is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R³ is optionally bonded to a carbon atom or a hetero atom on the aryl group or the heteroaryl group represented by A to form an optionally substituted ring structure, and Y is a single bond or an optionally substituted CM alkylene or an optionally substituted -O-

(CM alkylene)-,

R and R², or R² and R³ are optionally bonded to form an optionally substituted ring structure, provided that compounds represented by formulas

are excluded.

21. The use of at least one of Compound (J), a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for activating an AMP-activated protein kinase according to claim 20, wherein the at least one of Compound (J), a salt thereof, or a prodrug thereof is at least one of Compound (Ia), a salt thereof, or a prodrug thereof, wherein the Compound (Ia) is represented by a formula:

R^la and R²⁸, or R²⁸ and R^3a are optionally bonded to form an optionally substituted ring structure,

B^a is an optionally substituted benzene ring, and

C^a is an optionally substituted C_6-18 aryl group, or a salt thereof.

22. A use of N-{2-[4-({3-chloro4-[3-(trifluoromethyl) phenoxy]phenyl}amino)-5H- pyrrolo[3,2-d]pyrimidrn-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, a salt thereof, or a prodrug thereof for preparing a pharmaceutical composition for activating an AMP- activated protein kinase.