ZA200700208B

ZA200700208B - 5-amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2h-pyrido[2,3-D] pyrimidine derivatives and related compounds for the treatment of cancer

Info

Publication number: ZA200700208B
Application number: ZA200700208A
Authority: ZA
Inventors: Kawasaki Hisashi; Abe Hiroyuki; Hayakawa Kazuhide; Iida Tetsuya; Kikuchi Shinichi; Yamaguchi Takayuki; Nanayama Toyomichi; Kurachi Hironori; Tamaru Masahiro; Hori Yoshikazu; Takahashi Mitsuru; Yoshida Takayuki; Sakai Toshiyuki
Original assignee: Japan Tobacco Inc
Priority date: 2004-06-11
Filing date: 2005-06-10
Publication date: 2008-04-30

Description

5-AMINO-2,4,7-TRIOXO-3, 4,7, 8-TETRAHYDRO-2H-PYRIDO'2, 3-D! PYRIMIDINE DERIVATIVES

AND RELATED COMPOUNDS FOR THE TREATMENT OF CANCER

Technical Field

The present invention relates to a novel pyrimidine compound or a pharmaceutically acceptable salt thereof useful as an agent for the prophylaxis or treatment of diseases caused by undesirable cell proliferation, particularly, an antitumor agent.

Moreover, the present invention relates to novel use of a certain kind of pyrimidine compound or a pharmaceutically acceptable salt thereof as an agent for the prophylaxis or treatment of a disease caused by undesirable cell proliferation, particularly, as an antitumor agent. More particularly, the present invention relates to a pharmaceutical agent comprising a pyrimidine compound showing a pl5 protein inducing action and/or a p27 protein inducing action and/or an MEK inhibitory action, or a pharmaceutically acceptable salt thereof.

Background Art

A “cell cycle” means a cycle wherein the period for a cell to divide and once again divide is one cycle, and this cycle is also referred to as a “cell division cycle”.

A cell cycle includes four phases in a determined order.

They are DNA duplication preparation phase (Gl phase), DNA duplication phase (S phase), division preparation phase (G2 phase) and division phase (M phase), and regulated by many factors. Among them, the kinase activity of a cyclin/cyclin dependent kinase (CDK) complex is essential for the regulation of the cell cycle.

As a protein to inhibit the kinase activity, a CDK inhibitory protein is known. The CDK inhibitory proteins of mammalian cells are p2l family and plé family, both of which are considered to negatively regulate the progress of cell cycle and responsible for cell differentiation, apoptosis and repair of DNA damage due to irradiation of X ray and the like. At present, p21, p27 and p57 have been reported as a p2l family, and pl6, pl5, pis and pl9 have been reported as a pl6 family.

When these CDK inhibitory proteins are highly expressed in the cell, the cell proliferation is arrested at Gl phase.

The p21 family shows an inhibitory activity on a relatively wide range and plural cyclin/CDK complexes. For example, cyclin

E/CDK 2 which is an important cyclin /CDK complex from G1 phase " to G1/S transition phase, cyclin B/Cdc2 which is important for M phase and the like can be mentioned. The pl6é family is a specific inhibitory factor against cyclin D/CDK 4 and cyclin D/CDK 6, which are one of the cyclin/CDKs in the Gl phase, and is considered to dissociate the cyclin/CDK complex by binding with

CDK 4 and CDK 6, respectively.

From the examination of clinical materials of cancer of esophangus, pancreatic cancer, non-small cell lung cancer, skin cancer and the like, highly frequent incidence of genetic abnormality of P16 has been reported, and high cancer incidence in pl6 knock out mice has been demonstrated, and therefore, clinical application of pl6é inducer has been tried.

Under such situation, pl5 protein (aka:INK4B, also simply referred to as pl5) has been found as a pl6é family. In 1994, induction of pl5 expression by TGF—f stimulation was confirmed in human keratinocyte cell (HaCaT), and pl5 was considered to be one of the factors negatively regulating the cell cycle. It is known that induction of G1 phase cell cycle arrest in HaCaT by TGF-§ leads to the suppression of cell proliferation (Letters to Nature,

September 15, 1994, vol. 371, pp. 257-261).

While the histondeacetylase (HDAC) inhibitor is known *o arrest cell cycles at Gl phase or G2 phase in human cancer cell, it has been found recently that trichostatin A, which is an HDAC inhibitor, induces pl5 gene in human colon cancer cell (HCT116p21(-/-)), and the induction of pl5 by trichostatin A is involved in the inhibition of the cell proliferation of the cancer cells (FEBS Letters, 2003, vol. 554, pp. 347-350).

In this way, a compound that induces pl5 and/or p27 is expected to inhibit the cell proliferation of cancer cells and the like.

In the meantime, Mitogen-activated protein (MAP)

Kinase/extracellular signal-regulated kinase (ERK) kinase (hereinafter to be referred to as MEK) is known to be involved in the regulation of cell proliferation as a kinase that mediates

Raf-MEK-ERK signal transduction pathway, and the Raf family (B-

Raf, C-Raf etc.) activates the MEK family (MEK-1, MEK-2 etc.) and the MEK family activates the ERK family (ERK-1 and ERK-2).

Activation of Raf-MEK-ERK signal transduction pathway in cancer, particularly colorectal cancer, pancreatic cancer, lung cancer, breast cancer and the like, has been frequently observed.

In addition, since the signals produced by signal molecules such as growth factor, cytokine and the like converge to the activation of MEK-ERK, inhibition of these functions is considered to more effectively suppress Raf-MEK-ERK signal transduction than the suppression of the function of RTK, Ras,

Raf and the like in the upstream. :

Moreover, it is also known in recent years that a compound having an MEK inhibitory activity extremely effectively induces inhibition of ERK1/2 activity and suppression of cell proliferation (The Journal of Biological Chemistry, vol.276, No.4,

Pp.2686-2692, 2001), and the compound is expected to show effects on the disease caused by undesirable cell proliferation, such as tumor and the like. In addition, an MEK inhibitor is expected to inhibit infiltration or metastaticity of cells via promotion of expression of Matrix metalloproteinase (MMP) and CD44, and angiogenesis via promotion of expression of vascular endothelial growth factor (VEGF).

Furthermore, application to chronic pain (JP 2003-504401:

WO 01/005393), application to diseases or symptoms mediated by neutrophile (JP2002-332247: CA-2385412), application to graft rejection (JP 2002-532414: WO 00/35435) , application to arthritis (JP 2002-532415: WO 00/35436), application to asthma (JP 2002- 534380: WO 00/40235), application to viral diseases (JP 2002- 534381: WO 00/40237), application to diseases caused by deformation or injury of cartilage (W02002/087620: US 2004/138285), application to Peutz-Jeghers syndrome (W002/006520) are expected. ’

However, such pharmaceutical agent has not been marked heretofore. :

As an already commercially available antitumor agent, the following compound (Gefitinib) and the like are known (Iressa tablet 250 package insert).

L

2X

ENS

07 HN cl

M NGF

“0 7

JP-A-2004-504294 (patent family: WO2002/006213) describe the following compound and the like as compounds having an antitumor activity. In addition, the MEK inhibitory activity of such compounds is described (JP—A-2004-504294, pp. 123-124,

Example 39, Example 241).

XY

OH 0 HN

H

F

Known compounds relatively similar to the pharmaceutical agent of the present invention are described below.

Tn the literatures issued in 1991, the antitumor activity of pyrido[2.3-dlpyrimidine derivative has been studied and it is described, for example, that some of the following compounds and the like have an inhibitory activity in sarcoma, leukemia cells (Khimiia geterotsiklicheskikh soedinenii, 1991, No. 5, pp. 674- 680 (English translation p. 542, lines 4-7; p. 538, compound

Ilza)). 0 OH 0 es}

In the literatures issued in 1973, novel synthetic methods of the following compound and the like are disclosed and the antitumor activity of pyrido{2,3-d]pyrimidine derivative is described (Chem. Pharm. Bull., 1973, No. 21, vol. 9, pp. 2014- 2018 (p. 2015, chart 2, compound VIII)).

0 OM 0 ©

PES

0 N N 0

Me Ne

In these literatures, however, the compound of the present invention is not disclosed, nor is there found a description suggestive thereof.

Furthermore, W02002/094824 discloses the following compound and the like (W02002/094824, p. 55, Example 9) as a therapeutic agent having a cytokine regulating action for immune, inflammatory or allergic disease.

OH 0 Me

AY

Py N 0

Me H

In the literatures issued in 1996, synthetic methods of the following compound and the like are disclosed (Journal fur

Praktische Chemie, 1996, vol. 338, pp. 151-156 (p. 154, Table 1, compound 8f)).

F

CL 0 HN g

Py N~ 0 oh

In the literatures issued in 1986, synthetic methods of the following compound and the like as a synthetic intermediate for aminopterin analog having an antitumor activity are disclosed (Journal of Medicinal Chemistry, 1986, vol. 29, No. 5, pp. 709- 715 (p. 709 abstract; p. 712, Table 1, compound 9b)) . 0 Me

CN

0” N N 0

P H

MeO

However, this literature does not contain a description ) relating to the use of these compounds as antitumor agents, the compound of the present invention is not disclosed and a description suggestive thereof is not found.

Disclosure of the Invention

An object of the present invention is to provide a pharmaceutical agent containing a pyrimidine compound showing undesirable cell proliferation inhibitory action, particularly an antitumor action or a pharmaceutically acceptable salt thereof.

The present inventors have conducted intensive studies in an attempt to find a compound having such action and completed the present invention.

More particularly, the present invention provides the following (1) to (37). (1) Use of a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent for treating a tumor: 5 6 oS

RC MA AR

N X [1]

AYN

R? R® wherein ~

Xx! and Xx? are the same or different and each is a carbon atom or a nitrogen atom, a

SN

HA _R xX 2

R® moiety is

: SN NP SN 4 4

N 0 x 0 rR , R or R®

R', R?, and R® are the same or different and each is ° a Ci-¢ alkyl group, . a Cz-¢ alkenyl group, wherein the Cig alkyl group and the Cp alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or — yn ov) wherein m is 0 or an integer of 1 to 4, ring Cy is a C3; carbon ring group or a heterocyclic group, wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the C;.i; carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B,

R3, RY, and R®> are the same or different and each is a hydrogen atom, a hydroxyl group, a Cig alkyl group, a C;.g alkenyl group, wherein the Ci.g alkyl group and the C,. alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, a Cz-12 carbon ring group or a heterocyclic group, wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the Cs.i2 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or

R? and R? are optionally linked to form a C;.; alkylene group, or R?

and R® are optionally linked to form a Ci-4 alkylene group, wherein group A is a group consisting of 1) a halogen atom, 2) a nitro group, 3) a cyano Jgroup, 4) a Ci;-s4 alkyl group, 5) -OR™ wherein RM is a hydrogen atom or a Ci alkyl group, 6) —SR* wherein R™ is a hydrogen atom or a Ci alkyl group, 7) ~NRPMRM wherein R* and R* are the same or different and each is a hydrogen atom or a Cis alkyl group, ' B) -COOR* wherein R® is a hydrogen atom or a Cis alkyl group, 9) —NRP®CORM wherein RM is a hydrogen atom or a Cis alkyl group,

R» is a Ci. alkyl group, a Cs_iz carbon ring group or a heterocyclic group, 10) -NRMCOORM wherein R* and R* are the same or different and each is a hydrogen atom or a Cis alkyl group, 11) a Csz-iz carbon ring group and 12) a heterocyclic group, wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 heterc atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, each of the Cis alkyl groups of the above-mentioned 4), RM, RM,

RP RM, R*, R™, RY, R® and R™ is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and each of the Cs.» carbon ring groups of the above-mentioned 11) and RY, and the heterocyclic groups of 12) and RY is optionally substituted by the same or different 1 to 5 substituents selected from the following group C group B is a group consisting of 1) a halogen atom, ‘ 2) a nitro group, 3) a cyano group, 4) a Cy-3 alkyl group, 5) a Cz-4 alkenyl group, 6) a Cz-4 alkynyl group, 7) -OR®! wherein R® is a hydrogen atom or a Ci alkyl group, 8) -SR®? wherein R® is a hydrogen atom or a Ci4 alkyl group,

9) -NR®R® wherein R®® is a hydrogen atom, a C;-4 alkyl group, a Cs- "12 carbon ring group or a heterocyclic group, and R®* is a hydrogen atom or a Ci-4 alkyl group, 10) -NRB°COR®® wherein R®® is a hydrogen atom or a Ci-; alkyl group, and R®® is a hydrogen atom, a Ci-¢ alkyl group, a Cs-12 carbon ring group or a heterocyclic group, 11) -NRP’COOR®® wherein R® and R®® are the same or different and each is a hydrogen atom or a Cj;., alkyl group, . 12) -NRP°CONRERB! wherein RP, RB!’ and R®"' are the same or different and each is a hydrogen atom or a Ci-4 alkyl group, © 13) —NRP2CONRP!?0RP! wherein RP!?, R®® and R®*® are the same or different and each is a hydrogen atom or a C;-4 alkyl group, 14) -NRB°S0,RP!® wherein RP!® is a hydrogen atom or a Ci; alkyl group, and RP is a C;-4 alkyl group, a Cs-1z carbon ring group or a heterocyclic group, 15) -S0,~RP!? wherein RP! is a Ci-4 alkyl group or a heterocyclic group, 16) -SO,NRPPRP!® wherein RP? and R®’ are the same or different and each is a hydrogen atom or a Ci;-4 alkyl group, 17) -P{=0) (R®%°) (R®®') wherein R®*’ and R*' are the same or different and each is a C;-4 alkyl group, 18) ~COOR®?? wherein R®?? is a hydrogen atom or a Ci-q alkyl group, 19) —-CONRBZ3RP? wherein RP?® and RP? are the same or different and each is a hydrogen atom or a Ci-4 alkyl group, 20) —NRBZ5SO,NRPZRP?’ wherein R®2°, R®® and R®’ are the same or different and each is a hydrogen atom or a Ci;4 alkyl group, 21) —-NRE2®SO,NRBZ°CONREPR®* wherein R®®, R®°, R®3® and R®*! are the same or different and each is a hydrogen atom or a C;-s alkyl group, } 22) a Cs.12 carbon ring group and 23) a heterocyclic group wherein each of the “Cig alkyl group” of the above-mentioned 4), and the Cia alkyl groups for R® to R®¥ is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A, each of the Cys alkenyl group of 5) and the Coq alkynyl group of 6) is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group A, the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and each of the Ci.1z carbon ring group of the above-mentioned 22),

RP} RP¢ and R™?, and the heterocyclic group of the above- mentioned 23), R®, R®®, R®® and R®’ is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and group C is a group consisting of 1) a halogen atom, 2) a cyano group, 3) a C;-4 alkyl group, 4) ~OR®* wherein R® is a hydrogen atom or a Cis alkyl group, 5) -NRR® wherein R¥ and R® are the same or different and each is a hydrogen atom or a Ci alkyl group, 6) —COOR® wherein R® is a hydrogen atom or a Cis alkyl group and 7) an oxo group. (2) A compound represented by the following formula [I'] or a pharmaceutically acceptable salt thereof: . A

R'~_ PIES NR eerox [1

Sy

RFR wherein

RY, R? and Ré are the same or different and each is a Cig alkyl group, a Ca-s alkenyl group, wherein the Ci;-g alkyl group and the Cae alkenyl group are optionally substituted by 1 to 3 substituents selected from group A of the above-mentioned (1), or — ao) m is an integer of 0 or 1 to 4, ring Cy is a Csz-1z carbon ring group or a heterocyclic group wherein the heterocyclic group is a saturated or unsaturated ring having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the Cj3.., carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of the above-mentioned (1), provided that, when the 5

AN

4

X XN

3 5 R moiety is (]

NG

N rR

IAN

N 0 rR ) . then R?®’ is not a methyl group, and when R*’ is a phenyl group, then R' is not a phenyl group, and other symbols are as defined in the above-mentioned (1). (3) Use of the above-mentioned (1), wherein the compound is represented by the following formula [I-1]: 5 R®

R

0 Sy . 1

RR R

YY [1-1] 0 \ 0

R® FR wherein each symbol in the formula is as defined in the above- mentioned (1). (4) Use of the above-mentioned (1), wherein the compound is represented by the following formula [I-2]: 6 5 R

R

0 > 1

RN

~~ 00 1 [1-2] 0 \ N 0

RRR wherein each symbol in the formula is as defined in the above—

mentioned (1). " (5) Use of the above-mentioned (1), wherein the compound is represented by the following formula [I-3]: . Ro 1

Sy z - [1-3]

Ay NN

SN wherein each symbol in the formula is as defined in the above- "mentioned (1y. (6) Use of the above-mentioned (1), wherein R' is a Ci alkyl group. (7) Use of the above-mentioned (1), wherein R' is — ay) v wherein m is 0, and ring Cy is a Cs-iz carbon ring group wherein the Cs.» carbon ring group is optionally substituted by 1 to 5 substituents selected from group B of the above- mentioned (1). (8) Use of the above-mentioned (1), wherein R° is a Css cycloalkyl group. (9) Use of the above-mentioned (8), wherein R' is a cyclopropyl group. (10) Use of the above-mentioned (1), wherein R® is — ano) ' wherein m is 0, and ring Cy is a Cs.i2 carbon ring group or a heterocyclic group wherein the Cs.,2 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of the above-mentioned (1). (11) Use of the above-mentioned (1), wherein R® is a Ci-¢ alkyl group. (12) Use of the above-mentioned (1), wherein R* is a hydrogen atom. (13) Use of the above-mentioned (1), wherein R®> is a hydrogen atom. (14) Use of the above-mentioned (1), wherein R® is

- — (CH) —( or) wherein m is 0, and ring Cy is a Cs.12 carbon ring group or a heterocyclic group wherein the Ci_;; carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of the above-mentioned (1). (15) Use of a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the production of an antitumor agent.

(16) Use of a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of inhibiting MEK.

(17) Use of a compound of the formula [I] of the above-mentioned

(1) or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of inducing pl5 protein.

(18) Use of a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agents for treating a disease caused by an undesirable cell proliferation. (19) Use of the above-mentioned (18), wherein the disease causing by an undesirable cell proliferation is rheumatism.

(20) Use of a compound of the formula [I] of the above-mentioned

(1) or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of inhibiting undesirable cell proliferation.

(21) Use of a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of regulating cell cycle.

(22) A pharmaceutical composition which comprises a compound of the formula [I'] of the above-mentioned (2) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

(23) A pharmaceutical composition for the treatment of a tumor, which comprises a compound of the formula [I] of the above—

mentioned (1) or a pharmaceutically acceptable salt thereof, and "a pharmaceutically acceptable carrier. (24) A pharmaceutical composition for treating a disease causing by an undesirable cell proliferation, which comprises a compound of the formula [1] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. (25) A commercial package comprising a pharmaceutical composition of the above-mentioned (23) and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for treating tumor. (26) A commercial package comprising a pharmaceutical composition of the above-mentioned (24) and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for treating disease causing by an undesirable cell proliferation. (27) Use of (a) a compound of the formula [I] of the above- mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with (b) at least one other antitumor compound, for the production of an antitumor agent. (28) Use of (a) compound of the formula [I] of the above- mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient and (b) at least one other antitumor compound, in combination, for the production of an antitumor agent. (29) A pharmaceutical composition comprising, as an active ingredient, (a) a compound of the formula [I] of the above- mentioned (1) or a pharmaceutically acceptable salt thereof and (b) at least one other antitumor compound, and a pharmaceutical acceptable carrier, in combination. (30) A kit for treating a tumor comprising (2) a pharmaceutical composition comprising , as an active ingredient, a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof and (b) a pharmaceutical composition comprising , as an active ingredient, at least one other antitumor agent, in combination. (31) An antitumor agent comprising a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt. thereof as an active ingredient.

(32) A MEK inhibitor comprising a compound of the formula [I] of " the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient. (33) A pl5 protein inducer comprising a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof as an active ingredient. (34) An antitumor agent comprising, as an active ingredient, (a) a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof, which is used in 70 combination with (b) at least one other antitumor compound. (35) An antitumor agent comprising, as an active ingredient, (a) a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof, and (b) at least one other antitumor compound, in combination. (36) The agent of the above-mentioned (34), wherein (a) a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof and (b) at least one other antitumor compound are administered to a mammal simultaneously or sequentially. (37) The agent of the above-mentioned (35), wherein (a) a compound of the formula [I] of the above-mentioned (1) or a pharmaceutically acceptable salt thereof and (b) at least one other antitumor compound are administered to a mammal simultaneously or sequentially.

Best Mode for Embodying the Invention

The definitions of each substituent and each moiety used in the present specification are as follows. xX! and X? are the same or different, and each is a carbon atom or a nitrogen atom, a

RF

Hoe 3

XT 3 A

R moiety is

Claims

Claims

1. Use of a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent for treating a tumor: 5 6 R R 0 Sy

RN. J A. AR C0 NT 0 RRR wherein X' and Xx? are the same or different and each is a carbon atom or a nitrogen atom, a 5 6 Ry 4 ya X XN Re moiety is [] 6 6 Ry AN Ne 4 4 R R 104 XC 4S ! a : vo 0 So R , rR: or Rg R', R?, and R® are the same or different and each is a Ci-¢ alkyl group, a Cg alkenyl group, wherein the C,_g alkyl group and the C,- alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, or -- : — ar) wherein m is 0 or an integer of 1 to 4, ring Cy is a Cs-1; carbon ring group or a heterocyclic group, wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, the Cs.;» carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, R}, R*, and R’ are the same or different and each is a hydrogen atom, a hydroxyl group, a C:-g alkyl group, a Cp-g alkenyl group, wherein the C;-g alkyl group and the C;.s alkenyl group are optionally substituted by 1 to 3 substituents selected from the following group A, a Cs-12 carbon ring group or a heterocyclic group, wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the Cs.1; carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from the following group B, or R® and R® are optionally linked to form a C:-; alkylene group, or R* and R®> are optionally linked to form a C:;-s4 alkylene group, wherein group A is a group consisting of 1) a halogen atom, 2) a nitro group, : 3) a cyano group, 4) a C,.4 alkyl group, 5) -OR™ wherein RM is a hydrogen atom or a Ci-s alkyl group, 6) —SRM wherein R* is a hydrogen atom or a Ci; alkyl group, 7) -NRMR™ wherein R® and R* are the same or different and each is a hydrogen atom or a C;-4 alkyl group, 8) —COORM™ wherein R™ is a hydrogen atom or a C;-4 alkyl group, 9) —NRMCOR? wherein R is a hydrogen atom or a Cis alkyl group, RY is a Cj-4 alkyl group, a Cs-;; carbon ring group or a heterocyclic group, 10) -NRMCOORM wherein R™ and RM are the same or different and each is a hydrogen atom or a C;-4 alkyl group, 11) a Cs3-;; carbon ring group and

12) a heterocyclic group,

. wherein the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, each of the Cis alkyl groups of the above-mentioned 4), RM, RM, R*, RM, rR, RM, RY, RM and R™ is optionally substituted by the same or different 1 to 3 substituents selected from the following group C, and each of the Cs;.i, carbon ring groups of the above-mentioned 11) and RY, and the heterocyclic groups of 12) and RY is optionally substituted by the same or different 1 to 35 substituents selected from the following group C group B is a group consisting of 1) a halogen atom, 2) a nitro group, 3) a cyano group, 4) a Cig alkyl group, 5) a Cz-4 alkenyl group, 6) a Cy4 alkynyl group, 7) -OR®! wherein R®' is a hydrogen atom or a C;-4 alkyl group, 8) —-SR®? wherein RP? is a hydrogen atom or a Ci-4 alkyl group, 9) -NR®*R®® wherein R® is a hydrogen atom, a Ci; alkyl group, a Cs- ,» carbon ring group or a heterocyclic group, and R® is a hydrogen atom or a Ci;-4 alkyl group, 10) —NRP°COR®® wherein R®® is a hydrogen atom or a C;.s alkyl group, and R®® is a hydrogen atom, a Ci-4 alkyl group, a Cs.i2 carbon ring group or a heterocyclic group, 11) -NR®’COOR®® wherein R®’ and R® are the same or different and each is a hydrogen atom or a C;-4 alkyl group, 12) -NRP’CONRBIRB! wherein R®, RP and R®' are the same or different and each is a hydrogen atom or a Ci4 alkyl group, 13) -NREY2CONRP'®ORP!* wherein R®2, R®™? and R®? are the same or different and each is a hydrogen atom or a C;4 alkyl group, 14) -NR®°SO,RP'® wherein RP! is a hydrogen atom or a Cis alkyl group, and R16 is a Ci_4 alkyl group, a Cs.12 carbon ring group or a heterocyclic group, 15) —S0,-R®Y’ wherein R®! is a C;-4 alkyl group or a heterocyclic group,

16) —SO,NRP!®RP!® wherein R®® and R®’ are the same or different and "each is a hydrogen atom or a Ci-s alkyl group, 17) —P(=0) (R®?%) (R®®*) wherein R®° and R®™' are the same or different and each is a Ci-4 alkyl group,

18) —-COORB??2 wherein RP?? is a hydrogen atom ox a Ci-4 alkyl group, 19) -CONRBZ*R®?* wherein R®*® and R®* are the same or different and each is a hydrogen atom or a Ci-; alkyl group,

20) —NRE°S0,NRP?°RP?’ wherein R®2°, R®°® and R®*?7 are the same or different and each is a hydrogen atom or a C:-4 alkyl group,

21) —-NREZSO,NRPP°CONRPR™® wherein R®?, R*?, B®’ and R®** are the same or different and each is a hydrogen atom or a Ci; alkyl group,

22) a Cs.;2 carbon ring group and 23) a heterocyclic group wherein each of the “Ci.g alkyl group” of the above-mentioned

4), and the C,_; alkyl groups for R® to R®¥® is optionally substituted by the same or different 1 to 3 substituents selected from the above-mentioned group 2,

each of the Cy_4 alkenyl group of 5) and the Cis alkynyl group of 6) is optionally substituted by +he same or different 1 to

3 substituents selected from the above-mentioned group A,

the heterocyclic group is a saturated or unsaturated ring group having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and each of the Cs-12 carbon ring group of the above-mentioned 22),

R®3, R® and R®!®, and the heterocyclic group of the above- mentioned 23), R®, R®, R*® and R®’ is optionally substituted by the same or different 1 to 5 substituents selected from the following group C, and group C is a group consisting of

1) a halogen atom,

2) a cyano group,

3) a C;-4 alkyl group,

4) -OR® wherein R® is a hydrogen atom or a Ci-4 alkyl group,

5) -NRE?R®® wherein R°? and R® are the same or different and each is a hydrogen atom or a C;-4 alkyl group, 6) —COOR®* wherein R°® is a hydrogen atom or a Cis alkyl group and 7) an oxo group.

2. A compound represented by the following formula [I’'] or a pharmaceutically acceptable salt thereof: 6 R R 0 Sw } R' J JR BY I i 0 nv Ri 0 RFR wherein 5 R', R” and R® are the same or different and each is a C6 alkyl group, a C,-¢ alkenyl group, wherein the C;-g alkyl group and the C,¢ alkenyl group are optionally substituted by 1 to 3 substituents selected from group A of claim 1, or m is an integer of 0 or 1 to 4, ring Cy is a Cs.» carbon ring group or a heterocyclic group wherein the heterocyclic group is a saturated or unsaturated ring having, besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and the C;.;; carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of claim 1, provided that, when the 6 Ry 4 A Ae aR X NEN ks moiety is 6 6 RA, N 4 R 1X N 0 Ie then R? is not a methyl group, and "when RY is a phenyl group, then R' is not a phenyl group, and other symbols are as defined in claim 1.

3. Use of claim 1, wherein the compound is represented by the following formula [I-11]: 5 6 R R 0 ~~ \ ! R RN TY [1-1] RASS RR wherein each symbol in the formula is as defined in claim 1.

4. Use of claim 1, wherein the compound is represented by the following formula {I-2]: 5 6 R R 0 ~ ; RS IAN ry [1-2] 0 ; ; 0 RR wherein each symbol in the formula is as defined in claim 1.

5. Use of claim 1, wherein the compound is represented by the following formula [I-3]: 5 6 R R 0 ~~ ! R RN re NT YN [1-3] A NY 0 N 0 R? IN wherein each symbol in the formula is as defined in claim 1.

6. Use of claim 1, wherein R! is a C,.¢ alkyl group.

7. Use of claim 1, wherein R® is — oro)

wherein m is 0, and ring Cy is a Cs-;2 carbon ring group wherein the Cs-;; carbon ring group is optionally substituted by 1 to 5 substituents selected from group B of claim 1.

8. Use of claim 1, wherein R' is a Cs-g cycloalkyl group.

9. Use of claim 8, wherein R! is a cyclopropyl group.

10. Use of claim 1, wherein R? is , er) ’ wherein m is 0, and ring Cy is a Ci-j2 carbon ring group or a heterocyclic group wherein the Ci-12 carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of claim 1.

11. Use of claim 1, wherein R® is a Ci¢ alkyl group.

12. Use of claim 1, wherein R* is a hydrogen atom.

13. Use of claim 1, wherein R® is a hydrogen atom.

14. Use of claim 1, wherein R® is — ou (®) wherein m is 0, and ring Cy is a Cs-;2 carbon ring group or a heterocyclic group wherein the Cs; carbon ring group and the heterocyclic group are optionally substituted by 1 to 5 substituents selected from group B of claim 1.

15. Use of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the production of an antitumor agent.

16. Use of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of inhibiting MEK.

17. Use of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of inducing pl5 protein. 0 18. Use of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agents for treating a disease causing by an undesirable cell proliferation. 75 19. Use of claim 18, wherein the disease causing by an undesirable cell preliferation is rheumatism.

20. Use of a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of inhibiting undesirable cell proliferation.

21. Use of a compound of the formula {I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient for the production of a pharmaceutical agent capable of . regulating cell cycle.

22. A pharmaceutical composition which comprises a compound of the formula [I'] of claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

23. A pharmaceutical composition for the treatment of a tumor, which comprises a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

24. A pharmaceutical composition for treating a disease causing - by an undesirable cell proliferation, which comprises a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

25. A commercial package comprising a pharmaceutical composition of claim 23 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for treating tumor.

26. A commercial package comprising a pharmaceutical composition of claim 24 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can or should be used for treating disease causing by an undesirable cell proliferation.

27. Use of (a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, which is used in combination with (b) at least one other antitumor compound, for the production of an antitumor agent.

28. Use of (a) compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and (b) at least one other antitumor compound, in combination, for the production of an antitumor agent.

29. A pharmaceutical composition comprising, as an active ingredient, (a) a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof and (b) at least one other antitumor compound, and a pharmaceutical acceptable carrier, in combination.

30. A kit for treating a tumor comprising (a) a pharmaceutical composition comprising , as an active ingredient, a compound of the formula [I] of claim 1 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutical composition comprising , as an active ingredient, at least one other antitumor agent, in combination.