ZA200610669B

ZA200610669B - Fused heterocyclic compound

Info

Publication number: ZA200610669B
Application number: ZA200610669A
Authority: ZA
Inventors: Ishikawa Tomoyasu; Taniguchi Takahiko; Banno Hiroshi; Seto Masaki
Original assignee: Takeda Pharmaceutical
Priority date: 2004-06-02
Filing date: 2005-06-01
Publication date: 2008-06-25
Also published as: CN1993362A; UA91508C2; CN1993362B

Description

DESCRIPTION

FUSED HETEROCYCLIC COMPOUND

Technical Field

The present invention relates to a fused pyrimidine compound having a growth factor receptor tyrosine kinase inhibitory activity, which is useful for the prophylaxis or treatment of cancer, a production method thereof and use thereof.

Background Art

The gene of cell growth factor and growth factor receptor is called a protooncogene and plays a key role in the pathology of human tumor. The epithelial cell growth factor receptor family (erbB) includes EGFR, HERZ, HER3 and HER4, which are type I receptor type tyrosine kinases. These erbB family 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 HERZ, and homeostatic activation of receptors are empirically known to transform cells.

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, TGFa 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 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 1 degeneration of cancer due to topical increase in the ligand concentration.

Many cancers are associated with the high expression of

EGFR or HER2. For example, breast cancer (20-30%), ovarian cancer (20-40%), non-small cell lung cancer (30-60%), colorectal cancer (40-80%), prostate cancer (10-60%), bladder cancer (30-60%), kidney cancer (20-40%) and the like can be mentioned. Moreover, receptor expression and prognosis are correlated, and receptor expression is a poor prognostic factor in breast cancer, non-small cell lung cancer and the like.

In recent years, clinical use of a humanized anti-HER2Z 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, W098/02437, WO00/44728), gquinazoline derivatives (e.g., WO02/02552, WO01/98277,

WO03/049740, WO03/050108), thienopyrimidine derivatives (e.g.,

WO03/053446) , aromatic azole derivatives (e.g., W098/03648,

WO01/77107, WO03/031442) and the like are known; however, there is no HER2 kinase inhibitory substance to the present that has been marketed as a therapeutic drug for cancer.

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

HN HN ys Q 0 " 3 Pn " DN Pon " 3 Pn

H H H

As a compound having a receptor type tyrosine kinase activity, the following pyrrolo[3,2-d]lpyrimidine derivative is known (W096/40142, W098/23613). $0

HO—\ =.

H

Furthermore, as to pyrazolo[4,3-dlpyrimidine derivatives, 3,5,7-trisubstituted pyrazolo[4,3-d]lpyrimidine 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 CDK1l/ cyclin B inhibitory activity (Bioorganic & Medicinal Chemistry Letters, 2003, 13, 2989-2992). Furthermore, synthesis of 3- methylpyrazolo([4,3-d]lpyrimidine derivatives has been reported (The Journal of Organic Chemistry, 1956, 21, 833-836).

Disclosure of the Invention

The present invention aims at providing a compound having a superior tyrosine kinase inhibitory action, which is low toxic and highly satisfactory as a pharmaceutical product.

The present inventors have conducted intensive studies and found that a compound represented by the following formula (I) and a salt thereof (sometimes to be referred to as compound (I) in the present specification) have a superior tyrosine kinase inhibitory action. Further studies have resulted in the completion of the present invention.

Accordingly, the present invention provides

[1] a compound represented by the formula:

X' - ol Iw ~

N H

H wherein W is C(R!) or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, xX! is -NR*-Y!-, -0-, -S-, -SO-, -S50,- or —CHR’- 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

Y! is a single bond or an optionally substituted C;.4 alkylene or an optionally substituted -0-(C;-s 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

R! and R?, or R? and R® are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas a am wo!

HN HN HN

NAA TYNAN HAA © A

H H H H are excluded, or a salt thereof,

[2] a prodrug of the compound of the above-mentioned [1],

[3] the compound of the above-mentioned [1], wherein W is C (RY ‘

[4] the 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, -0-, -0-(C;-3 alkylene)-, -NH- or -S—, and B is an aryl group, a heterocyclic group, a Css cycloalkyl group, a carbamoyl group, a ureido group, a Ces aryl-carbonyl group or a Ces aryl-C;., 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 X? is a single bond, -NH- or -0-, and R! is a hydrogen atom, a cyano group, or a Cis alkyl group, a Cg alkenyl group, a C;-s alkynyl group, a carbamoyl group, a Cis alkyl-carbonyl group, a Cs-s cycloalkyl group, a Ces aryl group, a Ces aryl-Ci-q alkyl group, a Ce-1s aryl-carbonyl group, a Csis aryl-C;-4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-C;4; alkyl group, a heterocycle-carbonyl group or a heterocycle-C;-q alkyl-carbonyl group, each of which is optionally substituted,

[6] the compound of the above-mentioned [3], wherein R? is a hydrogen atom or a Cig alkyl group, a C;s alkenyl group, a Cis alkynyl group, a carbamoyl group, a Ci-g alkyl-carbonyl group, a Cig alkylsulfonyl group, a Css cycloalkyl group, a Ces aryl group, a Cgig aryl-Ci4 alkyl group, a Ce-1s aryl-carbonyl group, a Cg1g aryl-Cy-4 alkyl-carbonyl group, a Ces aryl-sulfonyl group, a heterocyclic group, a heterocycle-C,.4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci,.4 alkyl-carbonyl group, each of which is optionally substituted,

[7] the compound of the above-mentioned [3], wherein x! is -NR3- wherein R® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group,

[8] the 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,

-0-, -0-(C,.3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a Cs. cycloalkyl group, a carbamoyl group, a ureido group, a Cgis aryl-carbonyl group or a Ce-1s aryl-Cy., alkyl-carbonyl group, each of which is optionally substituted;

R! is a group of the formula -X?-R* wherein X? is a single bond, -NH- or -0-, and R! is a hydrogen atom, a cyano group, or a Ci-s alkyl group, a Cz-g alkenyl group, a Cz alkynyl group, a carbamoyl group, a Cis alkyl-carbonyl group, a Css cycloalkyl group, a Ce1s aryl group, a Ce-1s aryl-Ci-q alkyl group, a Ce-1s aryl-carbonyl group, a Ce-1s aryl-Ci4 alkyl-carbonyl group, a heterocyclic group, a heterocycle-C-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ciy alkyl-carbonyl group, each of which is optionally substituted;

R? is a hydrogen atom or a Cis alkyl group, a Czs alkenyl group, a C,.g alkynyl group, a carbamoyl group, a Cis alkyl-carbonyl group, a Cj-g alkylsulfonyl group, a Css cycloalkyl group, a

Ce-1s aryl group, a Ces aryl-Ci4 alkyl group, a Ceg-18 aryl- carbonyl group, a Ce-13 aryl-Ci-4 alkyl-carbonyl group, a Ce-1s aryl-sulfonyl group, a heterocyclic group, a heterocycle-Ci_4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C,_4 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] the compound of the above-mentioned [1], wherein W is N,

[10] the compound of the above-mentioned [9], 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—, -O0-(Cy.3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a Css cycloalkyl group, a carbamoyl group, a ureido group, a Ce-1s aryl-carbonyl group or a Ces aryl-Ci., alkyl-carbonyl group, each of which is optionally substituted,

[11] the compound of the above-mentioned [9], wherein R®> is a hydrogen atom or a Cis alkyl group, a Cz-s alkenyl group, a Cz-s alkynyl group, a carbamoyl group, a Cig alkyl-carbonyl group, a Cs alkylsulfonyl group, a Cs-s cycloalkyl group, a Ce-1s aryl group, a Ce-18 aryl-Ciy alkyl group, a Ce-1s aryl-carbonyl group, a Cg13 aryl-C;-q4 alkyl-carbonyl group, a Ce-1g aryl-sulfonyl group, a heterocyclic group, a heterocycle-C;.4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci—4 alkyl-carbonyl group, each of which is optionally substituted,

[12] the compound of the above-mentioned [9], wherein x! is —NR3- wherein R® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group,

[13] the compound of the above-mentioned [9], wherein x! is —NR3- 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, wherein ¥Y? is a single bond, -0-, -0-(C;-3 alkylene)-, -NH- or -S5-, and B is an aryl group, a heterocyclic group, a Cs.g cycloalkyl group, a carbamoyl group, a ureido group, a Cs-1s aryl-carbonyl group or a Ces aryl-C;-4 alkyl-carbonyl group, each of which is optionally substituted;

R? is a hydrogen atom or a Ci-g alkyl group, a C,.g alkenyl group, a C,.s alkynyl group, a carbamoyl group, a Cis alkyl-carbonyl group, a Cis alkylsulfonyl group, a Css cycloalkyl group, a

Ce-1g aryl group, a Cs-1z aryl-Cig alkyl group, a Ces aryl- carbonyl group, a Ces aryl-Ci alkyl-carbonyl group, a Cs-1s aryl-sulfonyl group, a heterocyclic group, a heterocycle-Ci_4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ciq alkyl-carbonyl group, each of which is optionally substituted,

[14] the compound of the above-mentioned [9], wherein X' is ~NR?-;

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-, -0-(C;-3 alkylene)-, -NH- or -S—, and B is an aryl group, a heterocyclic group, a Cig cycloalkyl group, a carbamoyl group, a ureido group, a Ce-1s aryl-carbonyl group or a Ces aryl-C,_s 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 represented by the formula: 0) i” ~ JT \

N

2 Dee (la) =

N H

H 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'® and R?®, or R*® and R*® are optionally bonded to form an optionally substituted ring structure,

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

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

B® is an optionally substituted benzene ring, and

C® is an optionally substituted Ce-1s aryl group, or a salt thereof,

[16] a compound represented by the formula:

O

’ 3b

RS

R N

N XN

R™ \ | (Ib) =

N H

R™ and R?, or R® and R*® are optionally bonded to form an optionally substituted ring structure,

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

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

B® is an optionally substituted benzene ring, c® is an optionally substituted Cg.is aryl group, and 7° is an optionally substituted C;.3 alkylene group, or a salt thereof,

[17] a compound represented by the formula: 0) 3c

R~ =)

RZ N

N

1 TSN

R'S \ (lc) ~

N H

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

S atom,

R*® is 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,

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

B® is an optionally substituted benzene ring, and

C° is an optionally substituted heterocyclic group, or a salt thereof,

[18] a compound represented by the formula: rR RS \ <T) rR" N | BY (1d) ~~

N H

H 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

RY and R¥, or R®*® and R* are optionally bonded to form an optionally substituted ring structure,

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

B? is an optionally substituted benzene ring, c? is an optionally substituted heterocyclic group, and z% is an optionally substituted Ci.; alkylene group, or a salt thereof,

[19] a compound represented by the formula: 0 = e . 8°

RZ N

N

SN

N (le) =

N H

H wherein R?® is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R%® and R3® are optionally bonded to form an optionally substituted ring structure,

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

B® is an optionally substituted benzene ring, and

C® is an optionally substituted Ce-1s aryl group, or a salt thereof,

[20] a compound represented by the formula: 0) [=] 3f

RS

N rR?

N XN

N (If) =

N H

H wherein R*f is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R* and Rf are optionally bonded to form an optionally substituted ring structure,

Bf is an optionally substituted benzene ring, c' is an optionally substituted C¢-13 aryl group, and z%¥ is an optionally substituted Ci-3 alkylene group, or a salt thereof,

[21] a compound represented by the formula: 0 3g

R eT

R*

N pg (19)

SZ

N H

H wherein R?9 is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R?? and R*® are optionally bonded to form an optionally substituted ring structure,

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

BY is an optionally substituted benzene ring, and c? is an optionally substituted heterocyclic group, or a salt thereof,

[22] (i) 2-{2-[4-({3-chloro-4-[(3~ fluorobenzyl) oxylphenyl}amino) -5H-pyrrolo[3,2-dlpyrimidin-5- yl]ethoxylethanol, (ii) 2-{2-[4-({3-chloro-4-[3-

(trifluoromethyl) phenoxylphenyl}amino) -5H-pyrrolo[3,2- d]lpyrimidin-5-yl}ethoxylethanol, (iii) N-{2-[4-({3-chloro-4-{3- (trifluoromethyl) phenoxylphenyl}amino) -5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-3-hydroxy-3-methylbutanamide, (iv) N-{2-[4-({3-chloro-4-[3- (trifluoromethyl) phenoxylphenyl}amino)-5H-pyrrolo(3,2- dlpyrimidin-5-yllethyl}-2-(methylsulfonyl) acetamide, (v) N—{2-[4- ({3-chloro-4-[3- (trifluoromethyl) phenoxyl}phenyl}amino)-SH-pyrrolo(3,2- d]pyrimidin-5-yllethyl}-2-methyl-2-(methylsulfonyl)propanamide, (vi) 5-{2-[2- (tert-butylsulfonyl) ethoxy]ethyl}-N-{3-chloro-4- [3- (trifluoromethyl) phenoxy]lphenyl}-5H-pyrrolo[3,2- d]pyrimidin-4-amine, (vii) 2- (methylsulfonyl)-N-{2-[4- ({3-methyl-4-[3- (trifluoromethoxy)phenoxylphenyl}amino)-5H-pyrrolo[3,2- dlpyrimidin-5-yllethyl}acetamide, (viii) N-[2- (4—{[3-chloro—-4- (3-chlorophenoxy)phenyl]amino}-5H- pyrrolo(3,2-dlpyrimidin-5-yl)ethyl]-2- (methylsulfonyl)acetamide, or (ix) N-{2-[4-({3-chloro-4-[3- (trifluoromethoxy)phenoxylphenyl}amino)-5H-pyrrolo[3,2- d]pyrimidin-5-yllethyl}-2- (methylsulfonyl)acetamide, or a salt of any of them,

[23] a method of producing a compound represented by the formula: o"

R® SCT

Wo te 2

N H

H wherein each symbol is as defined in the above-mentioned [1], or a salt thereof, which comprises reacting a compound represented by the formula:

L

R2

N XN

Ww

Ol _L (11)

N H

H wherein L is a leaving group, and other symbols are as defined in the above-mentioned [1], or a salt thereof with a compound . 5 represented by the formula:

G—Xx"A (I) wherein G is a hydrogen atom or a metal atom, and other symbols are as defined in the above-mentioned [1], or a salt thereof,

[24] a pharmaceutical agent comprising a compound represented by the formula:

X' -~ 2

R N

NN

Ww t)

N H

H wherein W is C(R!) or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, x! is -NR®-Y!-, -0-, -S-, -SO-, -S0,- or -CHR’- 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 vy! is a single bond or an optionally substituted Ci, alkylene or an optionally substituted -0-(Ci-4 alkylene),

R' is a hydrogen atom or an optionally substituted group bonded »5s 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 the compounds represented by the formulas oa a wo!

HN HN HN oo CP " 3 Pn " 3 Pn " N Pon " N SP.

H H H H are excluded, or a salt thereof, or a prodrug thereof,

[25] the pharmaceutical agent of the above-mentioned [24] which is a tyrosine kinase inhibitor,

[26] the pharmaceutical agent of the above-mentioned [24] which is an agent for the prophylaxis or treatment of cancer,

[27] the pharmaceutical agent of the above-mentioned [26] wherein the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer or kidney cancer,

[28] a method for the prophylaxis or treatment of cancer in a mammal, which comprises administering, to sald mammal, an effective amount of a compound represented by the formula: x' oi

RZ SCT wo 1 —

N H

H wherein W is C(R') or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, x! is -NR3-Y!-, -0-, -S—, -SO-, -SO,- or —CHR’- 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

Y! is a single bond or an optionally substituted C;-4 alkylene or an optionally substituted -0-(C;-4 alkylene)-,

R' and R?, or R? and R® are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas oa we!

HN HN HN a ed a

NAA TYAN "NAA oN AAS

H H H H are excluded, or a salt thereof, or a prodrug thereof,

[29] use of a compound represented by the formula: ot

RAN NN wo Io ~~

N H

H wherein W is C(RY) or N,

A is an optionally substituted aryl group or an optionally substituted heteroaryl group, x! is -NR3-Y!'-, -0-, -S-, -SO-, -S0,— or -CHR’- 50 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

Y' is a single bond or an optionally substituted Ci-; alkylene or an optionally substituted -0-(Ci;-4 alkylene),

R! and R?, or R? and R® are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas a Jao 0

HN HN HN

Hh,

NAAN THAN "NAA oy A,

H H H H are excluded, or a salt thereof, or a prodrug thereof, for the production of an agent for the prophylaxis or treatment of cancer, and the like.

Furthermore, the present invention provides

[30] the compound of the above-mentioned [15], wherein

R*® is (i) a Ci. alkyl group, a C,.g alkenyl group, a Cz alkynyl group, a C;.g alkyl-carbonyl group, a Cis alkylsulfonyl group, a Cs-s cycloalkyl group, a Css aryl group, a Ce-is aryl-Ci;4 alkyl group, a Ce-1s aryl-carbonyl group, a Ces aryl-Ci,-4 alkyl- carbonyl group, a Ces aryl-sulfonyl group, a heterocyclic group, a heterocycle-C;.4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci-y 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, (c) optionally halogenated Ci-4 alkyl, (d) -(CH2)nQ, (e) -(CH;)qa—Z'- (optionally halogenated Ci-s alkyl), (f) ~ (CHp) n—2'-Cs.g cycloalkyl,

(g) = (CHg) n=2%~ (CH2) n=Q, (h) = (CH,)a—2%~ (CH) n~2'- (optionally halogenated Ci alkyl), (i) — (CHy) a~2%~ (CH) n~27-Cs-g cycloalkyl, (§) = (CHz)n—2'~ (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) —(CHz)n—2%-Ci-4 alkoxy, and (1) -(CHp)a-2%— (CHp) p=2'~ (CHp) n~2'~Ci-a alkyl wherein m is an integer of 0 to 4, n is an integer of 1 to 4,

Q is hydroxy, carboxy, cyano, nitro, ~NR°R’, ~CONR®R’, —0OCONH; or —-SO,NR°R’, 1s 7! is -O-, -CO-, ~-C(OH)R®-, -C(=N-OR’)~, —S-, -S0-, -50.-, _N(COR®) —, -N(COzR®)-, -N(SO,R’)-, —-CO-0-, -0O-CO-, -CO-NR®-, _NR®-CO-, —-NR®-~CO;—, -NR®-CO-NH-, -NR’-S0;—, or ~NR®-C (=NH) -NH-, 7? is -O-, -CO—, —C(OH)R®-, —-C(=N-OR’)-, -S-, —S0-, -50,~, -NR®-, _N (COR?) —, -N{COzR®)-, -N(SO;R’)-, —CO-0-, —0-CO-, ~CO-NR®-, —NR®-CO-, —NR®~CO;—, -NR®-CO-NH-, —NR°-C(=NH)-NH-, -NR®*~50,-, or -S0,-NR®~, (CH;)m and (CHz) pn are optionally substituted by 1 to 5 substituents selected from halogen, optionally halogenated Ci-4 alkyl and hydroxy, and when m or n is not less than 2, a subset —CHyCH,— of (CHz)m and (CH,), is optionally replaced by —~CH=CH- or —-C=C-,

R® and R’ are the same or different and each is a hydrogen atom or a C;-s alkyl group, OT R® and R’ are bonded to form, together with a nitrogen atom, a 3— to g8-membered saturated or unsaturated aliphatic heterocyclic group,

Rf is a hydrogen atom or a Cia alkyl group, and

R? is a Ci. alkyl group, or (ii) a carbamoyl group optionally having 1 or 2 Cig 2lkyl group (s) optionally substituted by substituent(s) selected 18

AMENDED SHEET 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,

[31] the compound of the above-mentioned [15], wherein

B® is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen, Ci-s alkyl, hydroxy-Ci-s alkyl and C;-4 alkyloxy;

C® is a phenyl group optionally substituted by 1 to 5 substituents selected from (1) halogen, (ii) optionally halogenated Ci-s alkyl, (iii) hydroxy-Ci-s alkyl, (iv) heterocycle-Ci-4 alkyl (preferably, 5- to 8-membered heterocycle-C;-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 Ci-4 alkyloxy, (vi) Cia alkyl-carbonyl, (vii) cyano, (viii) carbamoyl optionally substituted by C;-g alkyl, and (ix) Ci-¢ alkoxy-carbonyl;

R is (i) a hydrogen atom, (ii) a cyano group, Or (iii) a Ci-z alkyl group or a Cz alkenyl group, each of which is optionally substituted by —~NR8-CO- (CH,) n~NR®R’ 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 Ci-4 alkyl group, R® is a hydrogen atom or a Cig alkyl group, and when n is not less than 2, a subset -CH,CH,— of (CH), is optionally replaced by —-CH=CH-; and

R*® is a C;.g alkyl group, a Cz-g alkenyl group or a Cig alkynyl group, each of which is optionally substituted by substituent (s) selected from (a) hydroxy, (b) carboxy, (c) cyano, (d) optionally halogenated Cia alkyloxy, (e) -0O-(CHg)—OH, (f) -O-(CH;),-0O—-CO-NHz, (g) -O- (CH) n—O- (optionally halogenated C;.q4 alkyl), (h) -O- (CH) n—SO;- (optionally halogenated Cis alkyl), (i) -O-(CH,) n—S0;-Cg-1g aryl, (3) —O-(CHz) n—SO,— (CHz2) n—~OH, (k) -O-(CHz),—NR®*-CO-Ci, alkyl, (1) -O- (CHp) n~NR®-CO- (CH) ,—S0,-C1.4 alkyl, (m) -0- (CH;) n»~NR®-S0,- (optionally halogenated Ci-4 alkyl), (n) -CO-NR®- (CH) ,~OH, (0) -CO-NR®- (CHp),—SO,— (optionally halogenated Ci-¢ alkyl), (p) -CO-NR®-0-C;.4 alkyl, (q) -NR°R’, (r) -NR®-(CHz)a~OH, (s) -NR®- (CH) n—S0,-Ci-4 alkyl, (t) ~NR®-CO- (optionally halogenated C;-4 alkyl), (u) -NR®-CO- (CH) ,~OH, (v) -NR®-CO- (CHz) n—CN, (w) ~-NR®-CO- (CH) ,~NR°R’, (x) ~NR®-CO- (CHp) ,~0-Ci-4 alkyl, (y) -NR®-CO- (CH,),—SO- (optionally halogenated Cis alkyl), (z) —-NR®-CO-(CHz),-SO.- (optionally halogenated C;., alkyl), (aa) -NR®-CO- (CH,) ,-S03-C3.3 cycloalkyl, (bb) -NR®-CO- (CHz) z—NR®-S0;~C1-4 alkyl, (cc) -NR®-COz- (CH) ,—SO2—-Ci-s alkyl, (dd) -NR®-CO-NH- (CHz) n—S0;-Ci1-s alkyl,

(ee) ~NR®-CO-NH-0-C;_4 alkyl, (ff) -NR®-CO-NH- (CH;) ,—0-Ci-4 alkyl, (gg) -NR®-C(=NH)-NH-Ci.s alkyl, (hh) -NR®-S0,- (CHz) n—S0,-Ci-4 alkyl, (ii) -S-(CH2).-OH, (jj) -SO-(CHz),~-OH, (kk) -SO,;—-(CH2),~OH, 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, Ci—s alkyl, optionally oxidized Cis alkylthio, —-CO-C;-4 alkyl, -CO-0-Ci-4 alkyl, -CO-NH-C;-4 alkyl, —-CONH,, -S0,-C,.; alkyl, —-SO,-NH-Ci.4 alkyl, —SO;NH 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 Ci-4 alkyl group, R® is a hydrogen atom or a C;.4 alkyl group, (CH). are optionally substituted by halogenated Ci-4 alkyl or hydroxy, and when n is not less than 2, a subset -CH;CH;— of (CH;), is optionally replaced by -CH=CH-;

R% is a hydrogen atom or a Cis alkyl group; or

R!? and R?® are optionally bonded to form °_ Nv RN Nv ; or ; or

R? and R* are optionally bonded to form C;-;, alkylene optionally substituted by an imino group, particularly preferably, R* is a Cis alkyl group, a Cis alkenyl group or a C;.g alkynyl group (particularly, a Cig alkyl group), each of which is optionally substituted by substituent (s) selected from (a) hydroxy,

(b} carboxy,

(c) cyano,

(d) optionally halogenated Ci-4 alkyloxy,

(e) -O- (CH;),—OH (wherein (CH:), is optionally substituted by hydroxy},

(f) -0O- (CH) ,—0-CO-NHgz,

{g) —-0O-(CHz),—O- (optionally halogenated Ci-4 alkyl),

(h) -O- (CH,) n~—SO,—- (optionally halogenated C;-s alkyl),

(1) —-O-(CHz)n—S0;—Ce-18 aryl, (J) —O-(CHz)a—S0,~ (CHz) n~OH,

(k) —-O- (CHp)a—NR!*-CO-C;.4 alkyl,

(1) -O- (CHp) »~NR®-CO- (CH;) ,~S0Oz-Ci1-a alkyl,

(m) —-O- (CH) »~NR®*-SO,- (opticnally halogenated Ci.s alkyl),

(n) —CO-NR®- (CH) ,~OH, (0) —-CO-NR®-(CHz),—-SO,- (optionally halogenated C;_, alkyl),

(p) -CO-NR®-0-Ci-q alkyl,

(q) -NR°R’,

(r) -NR°- (CHz)n—OH,

(s) -NR®- (CHz),-S0,-C;-q alkyl, (t) -NR®-CO- (optionally halogenated Cia alkyl),

(u) —-NR®-CO- (CH;) ,~OH (wherein (CHz). is optionally substituted by optionally halogenated Ci-4 alkyl or hydroxy),

(v) -NR®-CO- (CHz)a~CN,

(w) —NR®-CO- (CH) »~NR°R’ (when n is not less than 2, a subset -CH,CH,— of (CHz), is optionally replaced by -CH=CH-),

(x) -NR®-CO- (CHp),—0-Ci-4 alkyl,

(vy) —NR®-CO- (CH) ,~SO- (optionally halogenated Ci-4 alkyl),

(z) -NR®-CO- (CHz) »—SO;— (optionally halogenated Ci-4 alkyl)

(wherein (CHz), is optionally substituted by Ci-q alkyl), (aa) -NR®-CO- (CHz)a,—S0,-Css cycloalkyl,

(bb) -NR®-CO- (CHp) n-NR?-S0,~Cy-4 alkyl,

(cc) -NR®-CO;- (CHz) n,=S50,-Ci-4 alkyl,

(dd) -NR®~CO-NH-(CHz),-S0,~Ci-s alkyl,

(ee) -NR®-CO-NH-0-Cy4 alkyl,

(ff) -NR®-CO-NH- (CHz),—0-Cy_4 alkyl, (gg) -NR®-C(=NH)-NH-C;-s alkyl, (hh) -NR®-S0,- (CHz) n~S0,-Ci-s alkyl, (ii) -S-{(CH,).—OH, (jj) —-SO-(CHz) OH, (kk) -S80,- (CH) ,-OH, 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, Ci-q alkyl, optionally oxidized Ci_4 alkylthio, -CO-Ci-s alkyl, —-CO-0-Ci-4 alkyl, -CO-NH-C;_q alkyl, -

CONH,, -S0,-Cj-4 alkyl, -SO0;-NH-Ci-a alkyl, -SO;NH; and the like), 75 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 Ci-4 alkyl group, R® is a hydrogen atom or a Ci-4 alkyl group, (321 the compound of the above-mentioned [15], wherein

B® is a benzene ring optionally substituted by 1 to 4 substituents selected from halogen and optionally halogenated

Ci-q alkyl; c® is a phenyl group substituted by 1 to 5 substituents selected from (1) halogen, (ii) optionally halogenated Ci-4 alkyl, (iii) hydroxy-Ci-s4 alkyl, (iv) heterocycle-Ci.4 alkyl (preferably, 5- to 8-membered heterocycle-Ci.s 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 Ci-s alkyloxy, (vi) cyano, and (vii) carbamoyl optionally substituted by Ci -g alkyl;

R' is a hydrogen atom;

R?® is a Cig alkyl group, a Cg alkenyl group or a Cz alkynyl group, each of which is substituted by substituent (s) selected from (a) hydroxy, (b) optionally halogenated Cj;-q alkyloxy, (c) —O-(CHz),—OH, (d) -0O-(CHz) n,—O-CO-NHz, (e) —-0O-(CH),-0-C;-q4 alkyl, (£) —-0O- (CH) n—S0;- (optionally halogenated C;-s alkyl), (g) —O-(CHz)q—S50,-Ce-18 aryl, (h) -O- (CHz) n,—S0,— (CHz) n~OH, (1) ~0- (CH,) ,~NR®-S0,- (optionally halogenated Ci;-4 alkyl), (§) —CO-NR®- (CHz) ,—OH, (k) -CO-NR®- (CHp),-SO,- (optionally halogenated Ci; alkyl), (1) -NR°R’, (m) —NR°- (CHz)a—CH, (n) -NR®- (CHz) n—S0,-Ci-4 alkyl, (0) -NR®-CO- (CH) ,—OH, (p) -NR®-CO~ (CH;),-0-Cy.s alkyl, (gq) -NR®-CO- (CH) ,—SO- (optionally halogenated Cis alkyl), (r) -NR®-CO- (CH;),-SO,- (optionally halogenated C;_4 alkyl), (s) —-NR®-CO- (CHz),—S0O,-Cs.s cycloalkyl, (t) -NR®-CO,- (CH;) n~S0,-C;-q alkyl, (u) —NR®-CO-NH- (CHz),—S0,-Ci-4 alkyl, (v) -NR®]-S0,- (CH) n—S02~-Ci-4 alkyl, (w) —-S—(CHz)n~OH, (x) —-SO-(CHz)n—-OH, (y) —SOz— (CH) »—OH, and (z) -NR®}-CO- (optionally substituted heterocyclic group) (preferably, said heterocyclic group is a 5- to B-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, Ci-s alkyl, optionally oxidized C4 alkylthio, -CO-Ci;-¢ alkyl, —-CO-NH-C;.4 alkyl, -CONHz, -S0,~C1-4 alkyl, -SO,-NH-Cj;-s alkyl, -SO,NH, 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 C;-¢4 alkyl group, R® is a hydrogen atom or a Ci-s alkyl group, and (CHz), is optionally substituted by C;-; alkyl or hydroxy;

R** is a hydrogen atom or a Ci. alkyl group; or

R' and R® are optionally bonded to form 5 Ny a No or ; or

R*® and R* are optionally bonded to form Cj; alkylene, particularly preferably, R*® is a C,.g alkyl group, a Cag alkenyl group or a Cp.g alkynyl group (particularly, a Cie alkyl group), each of which is substituted by substituent (s) selected from (a) hydroxy, (b) optionally halogenated C;-q alkyloxy, (c) -O-(CHz),—OH (wherein (CH). is optionally substituted by hydroxy) , (d) -0-(CH;),—0-CO-NHg, (e) —-O-(CHz),—0-Ci-4 alkyl, (f) -O-(CHz)a—SO;- (optionally halogenated C;-q alkyl), (g) —0-(CHz)s—S0;-Cs-18 aryl, (h) —-O-(CH2)n—SO;~ (CHz) n—OH, (i) -O-(CHz)n~NR®-S0;- (optionally halogenated Ci-4 alkyl), (§) -CO-NR®°- (CH;),—OH, (k) -CO-NR®- (CH,),-SO,- (optionally halogenated Cis alkyl), (1) -NR°R’, (m) -NR®- (CH) a—OH, (n) -NR®-(CHz),—S0,-Ci-s4 alkyl, (0) -NR®-CO- (CH;),~OH (wherein CH;), is optionally substituted by Ci-q alkyl), (p) -NR®-CO- (CHz) n—O-C;-4 alkyl, (g) -NR®-CO- (CH) ,~SO- (optionally halogenated Ci-q4 alkyl), (r) -NR®-CO- (CH;)n—S0;- (optionally halogenated C;-4 alkyl) (wherein (CH,;), is optionally substituted by Ci-4 alkyl), (s) -NR®-CO- (CH) n—S0;—Cs-g cycloalkyl, (t) -NR®-CO,- (CH) ,—S0,—Ci-s alkyl, (u) -NR®-CO-NH- (CH) n—S02—Ci-4 alkyl, (v) -NR®-S0,- (CH) ,—S0,-Ci-4 alkyl, (w) —S- (CH) 4—OH, (x) —SO-(CH;)»—OH, (y) —-SO,-(CH;),—OH, 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, Ci-s alkyl, optionally oxidized Ci. alkylthio, —-CO-C;-s alkyl, —~CO-NH-C;-4 alkyl, -CONH,;, —-S5S0;-Ci_s alkyl, —-SO,-NH-C;-4 alkyl, —-SONH; 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 C;-4 alkyl group, and R® is a hydrogen atom or a C;.a alkyl group,

[33] the compound of the above-mentioned [31], wherein »5 R?® is (i) a Cs. alkyl group substituted by hydroxy, (ii) a Cis alkyl group substituted by substituent (s) selected from (a) halogenated C;-s alkyloxy, (b) —0O-(CHz) »—OH, (c) —0O-(CHz),-0O-CO-NHz, (d) —-O-(CHz) ,~O— (optionally halogenated C;.4 alkyl), (e) -O-{CH;)n—SO,- (optionally halogenated C;-4 alkyl), (f) —-O- (CHz) n=50,—Cg-13 aryl, (g) -O- (CH,) ,-NR*-S0,~ (optionally halogenated Cis alkyl),

(h) -CO-NR®- (CH;) OH, (i) —CO-NR®- (CH,)n-SO,- (optionally halogenated Ci-4 alkyl), (3) ~NR®- (CHz) n—SO,—Ci-s alkyl, (k) -NR®-CO- (CH) n—OH, (1) -NR®-CO- (CH,),-0-Ci-4 alkyl, (m) -NR®-CO- (CH;),-SO- (optionally halogenated Ci-q alkyl), (n) ~-NR®-CO- (CH) ,—S0O,- (optionally halogenated C;-4 alkyl), (0) -NR®-CO- (CH) n—S80;-Cs-s cycloalkyl, (p) -NR®-CO,— (CH) ,—S02-Ci-a alkyl, (gq) -NR®.-CO-NH- (CHz),~SO,—Ci-4 alkyl, (r) -NR®-SO,- (CHj) n—S0,-Ci-s alkyl, (s) -S-(CHz),~OH, (t) —SO- (CHz)n—OH, (u) —-SO,— (CHz),~OH, 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, Ci-¢ alkyl, optionally oxidized Cig alkylthio, —-CO-Ci4 alkyl, -CO-NH-C;-4 alkyl, -CONH;, —SO;-Ci_4 alkyl, —-SO,-NH-C;-4 alkyl, —-SO:;NH: and the like), wherein n is an integer of 1 to 4, R® is a hydrogen atom or a

Cis alkyl group, and (CH), is optionally substituted by Ci, alkyl or hydroxy, (iii) a Cz-s alkenyl group optionally substituted by hydroxy, or (iv) a Cz-g alkynyl group optionally substituted by hydroxy, particularly preferably, R*® is (i) a Cs.g alkyl group substituted by hydroxy, (ii) a Ci-s alkyl group substituted by substituent (s) selected from (a) halogenated C;-q alkyloxy, (b) —O- (CH) ,—OH (wherein (CHz)n is optionally substituted by hydroxy) , (c) —0-(CHz)n—0-CO-NHz, (d) -0O- (CH,) ,»—O- (optionally halogenated Ci-s alkyl), (e) —O- (CH,)5-SO;— (optionally halogenated Ci-4 alkyl), (f) —0O-(CHz),-S0;-Ce-18 aryl, (g) -0- (CH) n—NR®*-S0,- (optionally halogenated C;-s alkyl), (h) -CO-NR®- (CH) ,—OH, (i) -CO-NR®- (CH) »—SO,— (optionally halogenated Ci-q alkyl), (3) -NR®- (CH) ,—S0,-Ci-s alkyl, (k) ~NR®-CO- (CH;) ,—OH (wherein (CHz)na is optionally substituted by C;-s alkyl), (1) -NR®-CO- (CH) »—0-Ci-4 alkyl, (m) -NR®-CO- (CH;),—SO- (optionally halogenated C;-, alkyl), (n) -NR®-CO- (CH) ,~SO;— (optionally halogenated Cia alkyl) (wherein (CHz), is optionally substituted by Ci -4 alkyl), (0) -NR®-CO- (CHz) »—S0,-C3-g cycloalkyl, (p) -NR®-CO,- (CH;) n~S02-Ci-1 alkyl, (g) -NR®-CO-NH- (CH) x—S0;-Ci-4 alkyl, (r) -NR®-SO;— (CH;),~S02-Ci-s alkyl, {s) —S-(CHz)n~OH, (t) —SO- (CH2)n—OH, (u) —-S0,- (CH) ,—OH, 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, Ci;-s alkyl, optionally oxidized Cj, alkylthio, =CO-Ci_s alkyl, —CO-NH-Ci-4 alkyl, -CONHz, -SO;-Ci alkyl, —SO,-NH-Ci-4 alkyl, —SO:NH; and the like), wherein n is an integer of 1 to 4, and R® is a hydrogen atom or a C;.4 alkyl group, (iii) a Cz-s alkenyl group optionally substituted by hydroxy, or

Claims

1. A compound represented by the formula: x' ~A WO BY 0 : ~ N H H wherein W is C(R') or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group, x! is -NR®-Y'-, -O-, -S-, -SO-, —-SO;~ or -CHR’- 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 ¥! is a single bond or an optionally substituted Cis alkylene or an optionally substituted -0O-(C;-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 R! and R?, or R? and R® are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas a a CL HN HN HN Po Po Po LL, H H H H are excluded, or a salt thereof.

2. A prodrug of the compound of claim 1.

3. The compound of claim 1, wherein W is C(RY).

4. The compound of claim 3, wherein A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y? is a single bond, -0-, —-0-(Cj-3 alkylene)~, -NH- or -S—, and B is an aryl group, a heterocyclic group, a Cs cycloalkyl group, a carbamoyl group, a ureido group, a Ces aryl-carbonyl group or a Ce aryl-Ci-a alkyl-carbonyl group, each of which is optionally substituted.

5. The compound of claim 3, wherein R! is a group of the formula -X?-R? wherein X? is a single bond, -NH- or -O-, and R* is a hydrogen atom, a cyano group, or a Cig alkyl group, a Cz-g alkenyl group, a C;-g alkynyl group, a carbamoyl group, a Ci-g alkyl~carbonyl group, a Css cycloalkyl group, a Ces aryl group, a Cg-1e aryl-Ci-4 alkyl group, a Ces aryl-carbonyl group, a Ce-1s aryl-Ci.4 alkyl~-carbonyl group, a heterocyclic group, a heterocycle-C;-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C;-4 alkyl-carbonyl group, each of which is optionally substituted.

6. The compound of claim 3, wherein R? is a hydrogen atom or a

C,.g alkyl group, a Cz-g alkenyl group, a C;-g alkynyl group, a carbamoyl group, a Cig alkyl-carbonyl group, a Cis alkylsulfonyl group, a Cis cycloalkyl group, a Ces aryl group, a Cgig aryl—-Ci-4 alkyl group, a Ceais aryl-carbonyl group, a Ce-1s aryl-C;-q alkyl-carbonyl group, a Ces aryl-sulfonyl group, a heterocyclic group, a heterocycle-C;.4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C,.4 alkyl-carbonyl group, each of which is optionally substituted.

7. The compound of claim 3, wherein X! is -NR®*- wherein R® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group.

8. The compound of claim 3, wherein A is an aryl group substituted by a group of the formula -Y?’-B and optionally 5s further substituted, wherein Y? is a single bond, -0-, -0-(Ci-3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a Css cycloalkyl group, a carbamoyl group, a ureido group, a Ce-13 aryl-carbonyl group or a Ce-13 aryl-Ci-q alkyl~-carbonyl group, each of which is optionally substituted; R! is a group of the formula -X?-R* wherein X? is a single bond, -NH- or -0-, and R! is a hydrogen atom, a cyano group, or a Ci-g alkyl group, a C;-g alkenyl group, a C;.s alkynyl group, a carbamoyl group, a Cj;-g alkyl-carbonyl group, a Css cycloalkyl group, a Ces aryl group, a Ces aryl-Ci.q4 alkyl group, a Ce-18 aryl-carbonyl group, a Ceais aryl-Ci.s alkyl-carbonyl group, a heterocyclic group, a heterocycle-C;-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C,., alkyl-carbonyl group, each of which is optionally substituted; R? is a hydrogen atom or a Cis alkyl group, a Cg alkenyl group, a Cy-g alkynyl group, a carbamoyl group, a C;.g alkyl-carbonyl group, a Cig alkylsulfonyl group, a Css cycloalkyl group, a Ce-18 aryl group, a Ce-13 aryl-Ci-s alkyl group, a Ce-1s aryl- carbonyl group, a Ce-1s aryl-C,.4 alkyl-carbonyl group, a Ce-1s aryl-sulfonyl group, a heterocyclic group, a heterocycle-C;.4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C;., alkyl-carbonyl group, each of which is optionally substituted; and Xx! is —-NR*- wherein R® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group.

9. The compound of claim 1, wherein W is N.

10. The compound of claim 9, 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-, -0-(C;-3 alkylene)-, -NH- or -S5-, and B is an aryl group, a heterocyclic group, a Css cycloalkyl group, a carbamoyl group, a ureido group, a Ce-1s aryl-carbonyl group or a Cg-1g aryl-Ci-q alkyl-carbonyl group, each of which is optionally substituted.

11. The compound of claim 9, wherein R® is a hydrogen atom or a Ci-g alkyl group, a Cg alkenyl group, a C;g alkynyl group, a carbamoyl group, a Cig alkyl-carbonyl group, a Cig alkylsulfonyl group, a Cs-g cycloalkyl group, a Ces aryl group, a Cg.1g aryl-Ci4 alkyl group, a Ces aryl-carbonyl group, a Ce-1s aryl-C;-, alkyl-carbonyl group, a Ce-1e aryl-sulfonyl group, a heterocyclic group, a heterocycle-C;-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-C;.4 alkyl-carbonyl group, each of which is optionally substituted.

12. The compound of claim 9, wherein x! is -NR3- wherein R? is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group.

13. The compound of claim 9, wherein X' is -NR3>- 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, wherein Y? is a single bond, -0-, -0-(C;-3 alkylene)-, -NH- or -S—, and B is an aryl group, a heterocyclic group, a Cig cycloalkyl group, a carbamoyl group, a ureido group, a Ces aryl-carbonyl group or a Ce-1s aryl-Ci-qs alkyl-carbonyl group, each of which is optionally substituted; R? is a hydrogen atom or a Ci.g alkyl group, a Cz alkenyl group, a C,.g alkynyl group, a carbamoyl group, a Cis alkyl-carbonyl group, a Ci-s alkylsulfonyl group, a Cs-g cycloalkyl group, a Ce-1s aryl group, a Ces aryl-Ciq alkyl group, a Ces aryl-

carbonyl group, a Ces aryl-Ci.s alkyl-carbonyl group, a Ces aryl-sulfonyl group, a heterocyclic group, a heterocycle-Ci-4 alkyl group, a heterocycle-carbonyl group or a heterocycle-Ci4 alkyl-carbonyl group, each of which is optionally substituted.

14. The compound of claim 9, wherein X' is -NR>-; A is an aryl group substituted by a group of the formula -Y2-B and optionally further substituted, wherein Y? is a single bond, -0-, -0-(C;_3 alkylene)-, -NH- or -S-, and B is an aryl group, a heterocyclic group, a Cs-g cycloalkyl group, a carbamoyl group, a ureido group, a Ceais aryl-carbonyl group or a Ce-1s aryl-Ci-q 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 represented by the formula: 0 i” L&T \ N XN TX (1a) = N H H 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 RY and R?®, or R%*® and R?® are optionally bonded to form an optionally substituted ring structure, R3® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, ox

R*® is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B® is an optionally substituted benzene ring, and C* is an optionally substituted C¢-;3 aryl group, or a salt thereof.

l6. A compound represented by the formula: JOR ple © \ N EASY TX (Ib) = N H H 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™ and R?®, or R*®® and R® are optionally bonded to form an optionally substituted ring structure, R® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R® is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, BP is an optionally substituted benzene ring, cP is an optionally substituted Ces aryl group, and 7° is an optionally substituted C;-3 alkylene group, or a salt thereof.

17. A compound represented by the formula:

O 3c oo] R JO T=) iy Sy N SY Rc \ | (Ic) ~ N H H 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!® and R?*®, or R*® and R*® are optionally bonded to form an optionally substituted ring structure, R*® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R* is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B® is an optionally substituted benzene ring, and C° is an optionally substituted heterocyclic group, or a salt thereof.

18. A compound represented by the formula: 0 IC od 3d RS rR“ N N XN rR \ | (1d) ~ N H H 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 RY and R¥, or R® and R* are optionally bonded to form an optionally substituted ring structure, R* is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R* is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B® is an optionally substituted benzene ring, c?® is an optionally substituted heterocyclic group, and z% is an optionally substituted C;-3; alkylene group, or a salt thereof.

19. A compound represented by the formula:

0) . R2® Sy 5 NN N PY (le) Nd H

H . wherein R?*® is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R®® and R®*® are optionally bonded to form an optionally substituted ring structure, R*® is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R*® is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, B® is an optionally substituted benzene ring, and C® is an optionally substituted C¢.13 aryl group, or a salt thereof.

20. A compound represented by the formula: (0) 1) N 3t R™ N RZ N NUN N (1D — N H H wherein R?f is an optionally substituted group bonded via a carbon atom or a sulfur atom, or R*® and R3 are optionally bonded to form an optionally substituted ring structure, R*f is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R*® is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, Bf is an optionally substituted benzene ring, cf is an optionally substituted Cs.13 aryl group, and zf is an optionally substituted Ci;.; alkylene group, or a salt thereof.

21. A compound represented by the formula: 0) = RY 3g N R* N XN N (19) ~ N H H wherein R* is an optionally substituted group bonded via a carbon atom or a sulfur atom, or

R*® and R* are optionally bonded to form an optionally substituted ring structure, R* is a hydrogen atom or an optionally substituted aliphatic hydrocarbon group, or R% is optionally bonded to a carbon atom of the adjacent phenyl group to form an optionally substituted ring structure, BY is an optionally substituted benzene ring, and Cc? is an optionally substituted heterocyclic group, or a salt thereof.

22. (i) 2-{2-[4-({3-Chloro-4-{[(3- fluorobenzyl) oxy] phenyl }amino) -5H-pyrrolo[3,2-d]pyrimidin-5- yllethoxy}ethanol, (ii) 2-{2-[4-({3-chloro-4-[3- (trifluoromethyl) phenoxy]phenyl}amino)-5H-pyrrolo(3,2- d]lpyrimidin-5-yl}ethoxy}ethanol, (1ii) N-{2-[4-({3-chloro—-4-[3- (trifluoromethyl) phenoxylphenyl}amino) -5SH-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}~3-hydroxy—-3-methylbutanamide, (iv) N-{2-[4-({3-chloro-4-[3- (trifluoromethyl) phenoxy]phenyl}amino) -5H-pyrrolo[3,2- d]pyrimidin-5-yl]ethyl}-2-(methylsulfonyl) acetamide, (v) N-{2-[4~({3-chloro-4-[3- (trifluoromethyl) phenoxylphenyl}amino) -5H-pyrrolo[3,2- d]lpyrimidin-5-yllethyl}-2-methyl-2- (methylsulfonyl)propanamide, (vi) 5-{2-[2-(tert-butylsulfonyl)ethoxylethyl}-N-{3-chloro-4- [3- (trifluoromethyl) phenoxylphenyl}-5H-pyrrolo[3,2- d]lpyrimidin-4-amine, (vii) 2- (methylsulfonyl)-N-{2-[4- ({3-methyl-4-[3- (trifluoromethoxy)phenoxylphenyl}amino)-5H-pyrrolo[3,2- dlpyrimidin-5-yl]lethyl}acetamide, (viii) N-[2-(4-{[3-chloro-4- (3-chlorophenoxy)phenyl]lamino}-5H- pyrrolo[3,2-d]pyrimidin-5-yl) ethyl] -2- (methylsulfonyl) acetamide, or

(ix) N-{2-[4-({3-chloro-4-[3~ (trifluoromethoxy) phenoxylphenyl}amino)-5H~-pyrrolo[3,2- dlpyrimidin-5-yljethyl}-2- (methylsulfonyl)acetamide, or a salt of any of them.

23. A method of producing a compound represented by the formula: A X 2 R N ASV w (1 ~ N H H wherein each symbol is as defined in claim 1, or a salt thereof, which comprises reacting a compound represented by the formula: L RZ N IN WO LL (11) N H H wherein L is a leaving group, and other symbols are as defined in claim 1, or a salt thereof with a compound represented by the formula: G—X"-A (II) wherein G is a hydrogen atom or a metal atom, and other symbols are as defined in claim 1, or a salt thereof.

24. A pharmaceutical agent comprising a compound represented by the formula:

0 WO J C ~ N H H wherein W is C(R!) or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group, X' is -NR®-Y!'-, -0-, -S—-, -S0-, -SO,— or —CHR’- 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 Y' is a single bond or an optionally substituted C;.4 alkylene or an optionally substituted -O-(Ci.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 R' and R?, or R? and R® are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas a a CL HN HN HN " Po » Pi " PN ny H H H H are excluded, or a salt thereof, or a prodrug thereof.

25. The pharmaceutical agent of claim 24 which is a tyrosine kinase inhibitor.

26. The pharmaceutical agent of claim 24 which is an agent for tha prophylaxis or treatment of cancer.

27. The pharmaceutical agent of claim 26 wherein the cancer is breast cancer, prostate cancer, lung cancer, pancreatic cancer or kidney cancer.

28. Use of a compound represented by the formula: x - Sr W J (D = N H .

H . wherein W is Cc (RY or N, A is an optionally substituted aryl group or an optionally substituted heteroaryl group, x! is -NR’-Y'-, -0-, -S—, —-S50-, —SO,~ or -CHR’- 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 Y! is a single bond or an optionally substituted C;-a alkylene or an optionally substituted -0-(Ci-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 R! and R?, or rR? and R® are optionally bonded to form an optionally substituted ring structure, provided that the compounds represented by the formulas 538 AMENDED SHEET a.

Jose ie — HN HN HN ~ H H H ad H N Cl H \ H \ H AN HO N . A A, A H H H H are excluded, or a salt thereof, or a prodrug thereof, for the production of an agent for the prophylaxis or treatment of cancer.

540 AMENDED SHEET

ON HN HN HN ICL H H H H N XN N IN N XN N XN Ng Ao TN | A HQ Amo I N H N H H H H H H H are excluded, or a salt thereof, or a prodrug thereof, for the production of an agent for the prophylaxis or treatment of cancer.