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(11) Patent Number: KE 406

(21)Application Number:KElP/ 2009/ 000894

(22) Filing Date:18/1012007

(30) Priority data: 2006-285551  19/1012006  JP

(86) PCT data PCT/JP07/070772 18/1012007 W0/2008/050821 0210512008
 
(73) 0wner:TAKEDA PHARMACEUTICAL COMPANY LIMITED of 1-1, Doshomachi 4-chome Chuo-ku, Osaka-shi, Osaka 541-0045, JAPAN.

(72) Inventor: YASUMA, Tsuneo of 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka, 5410045,.Japao; UllKAWA,  Osamu of 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka, 5410045, Japao; ITOH, Maaahiro of 1-1, Doshomachi 4-chome, Chuo-ku, Osaka-shi, Osaka,  5410045, Japan and AOKI, Kazuko of 1-1, Doshomachi 4-<'home, Chuo-ku, Osaka-shi, Osaka, 5410045, Japan.

(74) Agent/address for correspondence:  Hamilton Harrison & Mathews, ICEA Building, KenyattaAvenue, P.O. Box 30333-00100, Nairobi
 
(54) Title:  INDOLE COMPOUND.

(57) Abstract:  The purpose of the present invention is to provide a glucokinase activator useful as a pharmaceutical agent such as an agent for the prophylaxis or treatment of diabetes, obesity and the like. The present invention provides a glucokinase activator containing a compound represented by the fonnula

(!):wherein Rl is a hydrogen atom or a halogen atom; R2 is a group represented by wherein each symbol is defined in the specification, or a salt thereof or a prodrug thereof.

DESCRIPTION

INDOLE  COMPOUND

Technical  Field

The present invention relates to a indole compound having a glucokinase activating action and useful as a therapeutic agent for diabetes and the like.

Background  Art

Glucokinase    {sometimes  to  be  abbreviated  to  as  GK  in  the

10    present specification) {EC2. 7 .1.1) is one of the four kinds of hexokinases found in mammals, and is also called hexokinase IV. GK is an enzyme that catalyzes the conversion of glucose to glucose-6-phosphate 1 which is the first step of glycolysis. GK is mainly present in the pancreatic 13 cell and the liver, and

15    acts in the pancreatic 13 cell as a sensor of extracellular glucose concentration that defines the glucose-stimulated insulin secretion. In the liver, the enzyme reaction of GK becomes a rate determining factor and regulates glycogen

synthesis  and  glycolysis.   The  three  hexokinases   {I,   II,  III)

20    other than GK reach the maximum enzyme activity at a glucose concentration of 1 mM or below. In contrast, GK shows low affinity for glucose and has a I<lu value of 8-15 mM. which is close to a physiological blood glucose level. Accordingly 1 GK-

mediated  promotion  of  intracellular  glucose  metabolism  occurs,

25    which corresponds to blood glucose changes from normal blood glucose (5 mM) to postprandial hyperglycemia (10-15 mM).

The  hypothesis  proposed  by  Matschinsky  et  al.  in  1984

that  GK  acts  as  a  glucose  sensor  in  the  pancreatic  13  cell  and

hepatocytes  has  been  demonstrated  by  the  analysis  of

30    glucokinase transgenic mouse in recent years (see The Journal of Biological Chemistry (J. Biol. Chern.), 1995, vel. 270, page 30253-30256; The Journal of Biological Chemistry (J. Biol.

Chern.), 1997 1 vol. 272, page 22564-22569; The Journal of Biological Chemistry (J. Biol. Chern.) 1 1997 1 vol. 272, page
35    22570-22575;  NIHONRINSHO,   2002,  vol.   60,  page  523-534;  and


Cell, 1995, vol. 83, page 69-78). That is, GK heterozygous deficient mouse showed a hyperglycemic condition, and further, a disordered glucose-stimulated insulin secretion response. GK homozygous deficient mouse dies shortly after birth with

s    manifestations of marked hyperglycemia and urinary sugar. On the other hand, GK overexpressed mouse (hetero type) showed decreased blood glucose level, increased blood glucose clearance rate, increased liver glycogen content and the like.

From  these  findings,   it  has  been  clarified  that  GK  plays  an

10    important role in the systemic glucose homeostasis. In other words, decreased GK activity causes insulin secretion failure and lower liver glucose metabolism, which develops impaired glucose tolerance and diabetes. Conversely, GK activation or

increased  GK  activity  due  to  overexpression  causes  promoted

15    insulin secretion and promoted liver glucose metabolism, which in turn increases the systemic use of glucose to improve

glucose  tolerance.

In addition, it has been clarified from the analysis of a report on GK gene abnormality mainly in the family of MODY2

20 (Maturity Onset Diabetes of the Young) that GK also acts as a glucose sensor in human, and plays a key role in glucose homeostasis (see Nature, 1992, val. 356, page 721-722). In GK gene abnormality, due to the decreased affinity of GK for glucose (increased Km value) and decreased Vmax, the blood

25    glucose threshold value of insulin secretion increases and the insulin secretory capacity decreases. In the liver, due to the decreased GK activity, decreased glucose uptake, promoted

gluconeogenesis, decreased glycogen synthesis and liver insulin resistance are observed. On the other hand, a family

30    with a mutation increasing the GK activity has also been found. In such family, fasting hypoglycemia associated with increased plasma insulin concentration is observed (see New England Journal Medicine, 1998, val. 338, page 226-230).

As  mentioned  above,  GK  acts  as  a  glucose  sensor  in

35    mammals  including  human,  and  plays  an  important  role  in  blood

glucose regulation. On the other hand, control of blood glucose utilizing the glucose sensor system of GK is considered to open a new way to treat diabetes in many type diabetes patients. Particularly, since a GK activating

5    substance is expected to show insulin secretagogue action in the pancreatic J3 cell and glucose uptake promotion and glucose release suppressive action in the liver, it will be useful as a prophylactic or therapeutic drug for type 2 diabetes.

In  recent  years,  it  has  been  clarified  that  pancreatic  J3

10 cell type glucokinase expresses locally in the feeding center (Ventromedial Hypothalamus: VMH) of rat brain. A subset of nerve cell present in VMH is called glucose responsive neuron, and plays an important role in the body weight control. From electrophysiological experiments, the neuron is activated in

15    response to physiological changes in the glucose concentration (5-20 mM). However, since the glucose concentration sensor

system of VHM is assumed to have a mechanism mediated by glucokinase as in the case of insulin secretion in the pancreatic J3 cell, different from pancreatic J3 cell and the

20    liver, a pharmaceutical agent capable of activating glucokinase of VHM has a possibility of providing not only a blood glucose corrective effect but also improvement of

obesity.

As  mentioned  above,  a  pharmaceutical  agent  capable  of

25    activating GK is useful as a prophylactic or therapeutic drug for diabetes, diabetic complications, and obesity.

As the indole compound, the following compound has been reported.

(1)    It  has  been  reported  that  a  compound  represented  by  the

30    formula:

Q-w-so,x-Q
'0

wherein

ring  A  is  an  optionally  substituted  monocyclic  or  bicyclic

aromatic  ring;

ring  B  is  an  optionally  substituted  6-membered  unsaturated

s    hydrocarbon ring or an optionally substituted 6-membered unsaturated heterocycle containing one nitrogen atom;

ring  C  is  an  optionally  substituted  5-membered  heterocycle

containing one or two nitrogen atoms; W is a single bond or -CH=CH-;

10    X  is  -N {R1 ) -   or  an  oxygen  atom;

Y  is  a  carbon  atom  or  a  nitrogen  atom;

Z  is  -N {R2 ) -   or  a  nitrogen  atom;  and

R1 and R2 are the same or different and each is a hydrogen atom or lower alkyl

15    is useful as an anti tumor agent or an angiogenesis inhibitor (see WO 95/07276 and JP-A-2000-309534).

(2)    It has been reported that a compound represented by the formula:
:m•'•')-
,.    il

20    wherein

R1 , R2 , R3 , R4 , R6 and R7 are each independently a hydrogen atom, a halogen atom, a nitro group, -CN, -OH, -COOH, -CF3 , -NR10 R11 (wherein R10 and R11 are each independently a hydrogen atom, a
C1- 6   alkyl  group,   -S02CH3   etc.),  a  C1 - 6   alkyl  group,  a  C3-s

25    cycloalkyl group, a heteroaryl group and the like; R5 is a C1 - 6 alkyl group and the like; and
A  is  an  optionally  substituted  thiazolyl  and  the  like,

is useful as a glucokinase activator (see W02005/049019). However, none of the above-mentioned prior articles

JO    discloses  the  following  formula   (I).


Disclosure  of  the  Invention

The  purpose  of  the  present  invention  is  to  provide  a

glucokinase  activator  which  is  useful  as  a  pharmaceutical

s    agent such as agents for the prophylaxis or treatment of diabetes, obesity and the like, and the like.

The present inventors have conducted intensive studies and found that a compound represented by the formula (I):

R'~R' (I)
R'Ar'-{

RLso;-W

10    wherein

R1 is a hydrogen atom or a halogen atom; R2 is a group represented by

or

wherein

15    A  is  CH  or  N;

R4 and R5 are each independently an optionally substituted C1- 6 alkyl group or an optionally substituted C3- 10 cycloalkyl group, or R4 and R5 in combination form an optionally

substituted  ring  wherein  the  ring  should  not  be  morpholine;

20    and

R6 , R7 , R21 and R22 are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group or an acyl group, or R6 and R7 in combination form an optionally substituted ring;

25    W is 0 or NR8 wherein R8 is a hydrogen atom, an optionally substituted C1 - 6 alkyl group or an optionally substituted C3_ 10 cycloalkyl group;

R3 is an optionally substituted heterocyclic group or an optionally substituted C&-14 aryl group; and
 




R9 , R10 and R11 are each independently a hydrogen atom, a halogen atom, an optionally substituted C1 - 6 alkyl group or optionally substituted C1 - 6 alkoxy group,

provided  that

a compound wherein R 21 is a hydrogen atom or a C1- 6 alkoxy-carbonyl group, R22 is a hydrogen atom, and R6 and R7 are both hydrogen atoms, and

a compound wherein R21 is a hydrogen atom or a C1_6 alkoxy-carbonyl groug, R22 is a hydrogen atom, and R6 and R7 are

10 both methyl groups are excluded,

or  a  salt  thereof   [hereinafter  to  be  abbreviated  as  compound

(I)]

unexpectedly  has  a  superior  glucokinase  activating  action  as

15    well as superior properties as a pharmaceutical product such as stability and the like, and can be a safe and useful as a pharmaceutical agent, which resulted in the completion of the

present  invention.

Accordingly,    the  present  invention  relates  to

20    [1]   compound  {I);

[2]    the compound of the above-mentioned [1], which is a compound represented by the formula {I):

(I)

wherein

25    R1 is a hydrogen atom or a halogen atom; R2 is a group represented by

---{11~-R' ...    or   
N.A   Rs. __ /       
       

wherein

A  is  CH  or  N;

30    R4 and  R5  are  each  independently  an  optionally  substituted

C1 - 6 alkyl group or an optionally substituted C3- 10 cycloalkyl group, or R4 and R5 in combination form an optionally substituted ring wherein the ring should not be morpholine;

and

R6 and R7 are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group an acyl group, or R6 and R7 in combination form an optionally substituted ring;

W is  0  or  NR8   wherein  R8   is  a  hydrogen  atom  or  an  optionally

10    substituted  C1 - 6   alkyl  group;

R3 is an optionally substituted heterocyclic group; and R9 , R10 and R11 are each independently a hydrogen atom, a
halogen  atom,   an  optionally  substituted  C1 _ 6   alkyl  group  or

optionally  substituted  C1- 6   alkoxy  group,

15    provided  that

a compound wherein R6 and R7 are both hydrogen atoms, and a compound wherein R6 and R7 are both methyl groups

are  excluded,

or  a  salt  thereof;

20    [3]  the  compound  of  the  above-mentioned  [1],  wherein  R2   is  a

group  represented  by
.•••,,
R6    :
---{tR':

N

wherein  R6  and  R7  are  as  defined  in  the  above-mentioned  [1];

[4]    the  compound  of  the  above-mentioned  [3],  wherein  R6   is  a  c 1_

25 6 alkyl group substituted by an optionally substituted heterocyclic group;

[5]    the compound of the above-mentioned [3], wherein R7 is a hydrogen atom;

[6]    the  compound  of  the  above-mentioned  [3],  wherein  R6   and  R7

30    in  combination  form  an  optionally  substituted  ring;

[ 7]  the  compound  of  the  above-mentioned  [ 3] ,  wherein  W is  NR8

wherein  R8   is  as  defined  in  the  above-mentioned  [1];

[8]    the  compound  of  the  above-mentioned  [3],  wherein  R3   is  a  5-

or  6-membered  monocyclic  aromatic  heterocyclic  group;

[9]    the compound of the above-mentioned [3], wherein R9 is a hydrogen atom or a halogen atom;

[10]    the  compound  of  the  above-mentioned  [3],  wherein  R10   is  a

5    hydrogen atom, a halogen atom, a C1 - 6 alkyl group or an optionally substituted C1- 6 alkoxy group;

[11]    the compound of the above-mentioned [ 3] , wherein R11 is a hydrogen atom, a halogen atom or a C1 _6 alkyl group;

[12]    N, N-dirnethyl-2- { 4- [ {2- { 7- [methyl {2-

10    thienylsulfonyl) amino] -1H-indol-2-yl}-l, 3-thiazol-5-yl) methyl] piperazin-1-yl} acetamide;

N-methyl-N- [2- (8-oxa-1-thia-3-azaspiro [ 4. 5] dec-2-en-2-yl) -1H-indol-7-yl] thiophene-2-sulfonamide;

N- [2- [ 4- (hydroxyrnethyl) -4, 5-dihydro-1, 3-thiazol-2-yl] -5- (2-

15    methoxyethoxy) -1H-indol-7-yl] -N-methylpyridine-2-sulfonamide; N-methyl-N-{2- [5- (morpholinomethyl) -4, 5-dihydro-1, 3-thiazol-2-yl] -1H-indol-7 -yl} thiophene-2-sulfonamide;

2- (2- { 7- [methyl (pyridin-2-ylsulfonyl) amino] -1H-indol-2-yl }-

4, 5-dihydro-1, 3-thiazol-5-yl) acetamide;

20    N- (difluoromethyl) -N-{ 2- [5- (morpholinomethyl) -4, 5-dihydro-1, 3-thiazol-2-yl] -1H-indol- 7-yl} thiophene-2-sulfonamide;

2- { 2- [7- [methyl (2-thienylsulfonyl) amino] -5- (trifluoromethoxy)-1H-indol-2-yl] -4, 5-dihydro-1, 3-thiazol-5-yl} acetamide;

N- (5- (2-methoxyethoxy) -2- { 5- [ (1-oxidothiomorpholino) methyl]-

25    4, 5-dihydro-1, 3-thiazol-2-yl} -1H-indol-7-yl) -N-methylpyridine-2-sulfonamide;

2- (2-{ 7- [methyl (2-thienylsulfonyl) amino] -1H-indol-2-yl} -1-

thia-3, 8-diazaspiro [ 4. 5] dec-2-en-8-yl) acetamide;  or

N- [2-{ 5- [ (1, 1-dioxidothiomorpholino) methyl] -4, 5-dihydro-1, 3-

30    thiazol-2-yl} -5- (2-methoxyethoxy) -1H-indol-7-yl] -N-methy l pyridine- 2 -sulfonamide;

salt  thereof;

[13]    a  prodrug  of  compound   (I);

[14]    a  glucokinase  activator  comprising  compound   (I)   or  a

35    prodrug  thereof;
 





[15)    a pharmaceutical agent comprising compound (I) or a prodrug thereof;

[16)    the  pharmaceutical  agent  of  the  above-mentioned   [15],

which  is  an  agent  for  the  prophylaxis  or  treatment  of  diabetes

5    or  obesity;

[17]    a method of activating a glucokinase in a mammal, which comprises administering compound (I} or a prodrug thereof to

the  rnarrunal;

[18]    a  method  for  the  prophylaxis  or  treatment  of  diabetes  or

10    obesity  in  a  mammal,  which  comprises  administering  compound

(I)    or  a  prodrug  thereof  to  the  mammal;

[19]    use of compound (I) or a prodrug thereof for the production of a glucokinase activator;

[20]    use  of  compound   (I)   or  a  prodrug  thereof  for  the

15    production of an agent for the prophylaxis or treatment of diabetes or obesity;

and  the  like.

Since compound (I) has a superior glucokinase activating action, compound (I) is useful as a pharmaceutical agent such

20    as an agent for the prophylaxis or treatment of diabetes, obesity and the like, and the like.

[Detailed  Description  of  the  Invention]

Unless  otherwise  specified,   as  the  "halogen  atom"  in  the

25 present specification, fluorine atom, chlorine atom, bromine atom or iodine atom can be mentioned.

Unless otherwise specified, as the "C1 - 3 alkylenedioxy group" in the present specification, methylenedioxy, ethylenedioxy or the like.

30 Unless otherwise specified, as the "C1_ 6 alkyl group" in the present specification, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl,

2, 2-dimethylbutyl,   3, 3-dimethylbutyl,   2-ethylbutyl  or  the  like.

35    Unless  otherwise  specified,  as  the  "C1 _ 6   alkoxy  group"  in
 





the  present  specification,  methoxy,   ethoxy 1     propoxy,

isopropoxy,    butoxy,   isobutoxy 1     sec-butoxy,  tert-butoxy  or  the

like.

Unless  otherwise  specified,  as  the  "C1 _6   alkoxy-carbonyl

5    group" in the present specification, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl or the

like.

Unless otherwise specified, as the "C1 _ 6 alkyl-carbonyl grouprr in the present specification, acetyl, propanoyl,

10    butanoyl, isobutanoyl, pentanoyl 1 isopentanoyl, hexanoyl or the like.


Each symbol in the formulas is described in detail in the following.

15    R1   is  a  hydrogen  atom  or  a  halogen  atom.

R1 is preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom.

R2   is  a  group  represented  by


or

20    wherein  each  symbol  is  as  defined  above.

R2   is  preferably  a  group  represented  by




wherein  each  symbol  is  as  defined  above,

more  preferably  a  group  represented  by
. ',
R6    :
---{j-R':
25    N
wherein  each  symbol  is  as  defined  above.

In  the  embodiment  wherein  R2   is  a  group  represented  by

R6 , R7 , R21 and R22 are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group or acyl group, or R6 and R7 in combination form an optionally

5    substituted  ring.

As the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R6 , R7 , R21 or R22 , for example, a C1 _10 alkyl group, a C2-1o alkenyl group, a C2 - 10 alkynyl group, a C3 - 10 cycloalkyl group, a C 3 - 10 cycloalkenyl group, a C4_ 10

10    cycloalkadienyl group, a C6- 14 aryl group, a C7- 13 aralkyl group, a Ca-13 arylalkenyl group, a C3 - 10 cycloalkyl-C1- 6 alkyl group and the like can be mentioned.

As used herein, as the C1- 10 alkyl group, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,

15    tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2, 2-dimethylbutyl, 3, 3-dimethylbutyl, 2-ethylbutyl, heptyl, cetyl, nonyl, decyl and

the  like  can  be  mentioned.

As  the  C2- 10   alkenyl  group,   for  example,  ethenyl,  1-

20    propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl and the like can be

mentioned.

25 As the C2- 10 alkynyl group, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl and the like can be mentioned.

30 As the C3-1o cycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned.


As the C3-1o cycloalkenyl group, for example, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl and the like can be mentioned.

As  the  C4-l0  cycloalkadienyl  group,   for  example,   2, 4-

5    cyclopentadien-1-yl,  2, 4-cyclohexadien-1-yl,  2, 5-

cyclohexadien-1-yl and the like can be mentioned. The above-mentioned C3-10 cycloalkyl group, C3- 10

cycloalkenyl group and C4-10 cycloalkadienyl are each optionally condensed with a benzene ring to form a fused cyclic group,

10    and as the fused cyclic group, for example, indanyl, dihydronaphthyl, tetrahydronaphthyl, fluorenyl and the like can be mentioned. In addition, as the aforementioned

hydrocarbon  group,   a  cross-linked  hydrocarbon  group  such  as

bicycle [2. 2 .1] heptyl,   bicycle [2. 2. 2] cetyl,   bicycle [3. 2 .1] cetyl,

15    bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, bicyclo[4.3.1]decyl, adamantyl, norbornanyl and the like, and

the  like  can  also  be  mentioned.

As  the  C6-14  aryl  group,   for  example,  phenyl,  naphthyl,

anthryl,    phenanthryl,   acenaphthylenyl,  biphenylyl  and  the  like

20    can  be  mentioned.   Of  these,   phenyl,  1-naphthyl,  2-naphthyl  and

the  like  are  preferable.

As  the  C7- 13  aralkyl  group,   for  example,  benzyl,  phenethyl,

naphthylmethyl, biphenylylmethyl and the like can be mentioned. As the Ca-13 arylalkenyl group, for example, styryl and

25    the  like  can  be  mentioned.

As the C3-10 cycloalkyl-C1-6 alkyl group, for example, cyclohexylmethyl and the like can be mentioned.

The C1-1o alkyl group, C2 - 10 alkenyl group and C2 - 10 alkynyl group exemplified as the aforementioned "hydrocarbon group"

30 optionally have 1 to 3 substituents at substitutable positions. As such substituents, for example,

(1)    a  C3 - 10   cycloalkyl  group   (e.g.,   cyclopropyl,   cyclohexyl);
(2)    a C6- 14 aryl group (e.g., phenyl, naphthyl) optionally substituted by 1 to 3 substituents selected from

35    (a)   a  C1- 6   alkyl  group  optionally  substituted  by  1  to  3
halogen  atoms,

{b)    a  hydroxy  group,

(c) a C1 - 6 alkoxy group, and {d) a halogen atom;

5 (3) optionally substituted heterocyclic group (those similar to the below-mentioned "optionally substituted heterocyclic group" for R3 can be mentioned);

(4) an amino group optionally mono- or di-substituted by substituent(s) selected from
(a) a C1- 6 alkyl group optionally substituted by 1 to substituents selected from a hydroxy group and a C1 _6 alkylsulfonyl group (e.g., methylsulfonyl),

(b)    a  C1- 6   alkyl-carbonyl  group,

(c)    a  C1- 6   alkoxy-carbonyl  group  optionally  substituted  by

15    to  3  C6- 14   aryl  groups   {e.g.,  phenyl),

(d)    a  C6- 14   aryl-carbonyl  group   (e.g.,  benzoyl),

(e)    a C7 - 13 aralkyl-carbonyl group (e.g., benzylcarbonyl, phenethylcarbonyl),

(f)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by

20    substituent(s) selected from a C1 - 6 alkyl group, a C6 - 14 aryl group (e.g., phenyl) and a C7 - 13 aralkyl group (e.g., benzyl),

(g)    a C1_ 6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl),
(h)    a  C6_ 14   arylsulfonyl  group  {e.g.,  benzenesulfonyl,  1-

25    naphthalenesulfonyl, 2-naphthalenesulfonyl) optionally substituted by 1 to 3 C1 - 6 alkyl groups,

(i)    a  C7 - 13   aralkylsulfonyl  group   (e.g.,  benzylsulfonyl)

(j)    a  C3 - 10   cycloalkyl  group  (e.g.,   cyclohexyl)   optionally

substituted  by  1  to  3  substituents  selected  from  a  hydroxy

30    group  and  a  C1- 6   alkyl  group,

(k)    an  aromatic  heterocyclic  group   (e.g.,  triazolyl),  and

(1)    a  non-aromatic  heterocyclic  group   (e.g.,

tetrahydrothiopyranyl,    1-oxidotetrahydrothiopyranyl,  1,1-

dioxidotetrahydrothiopyranyl);

35    (5)  an  arnidino  group;


(6)    a C1 _ 6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;

(7)    a C1 _ 6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms;

5 ( 8) an aromatic heterocyclyl-carbonyl group (e.g., thienylcarbonyl, indolylcarbonyl) optionally substituted by 1 to 3 amino groups [the amino groups are each optionally mono-or di-substituted by substituent (s) selected from a C1 _6 alkyl group and an aromatic heterocyclyl-sulfonyl group (e.g.,

10    thienylsulfonyl) ] ;

(9)    a non-aromatic heterocyclyl-carbonyl group (e.g., piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-oxidothiomorpholinylcarbonyl, 1, 1-

dioxidothiomorpholinylcarbonyl,    pyrrolidinylcarbonyl,

15    azetidinylcarbonyl} optionally substituted by 1 to 3 substi tuents selected from
(a)    a  hydroxy  group,

(b)    a  C1- 6   alkyl  group  optionally  substituted  by  1  to  3

hydroxy  groups,

20    (c)   a  halogen  atom,  and

(d)    a  carboxy  group;

(10} a C1_ 6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) optionally substituted by 1 to 3 halogen atoms; (11) a carbamoyl group optionally mono- or di-substituted by

25    substituent(s)   selected  from

(a)    a  C1 - 6   alkyl  group  optionally  substituted  by  1  to  3

substituents selected from a hydroxy group, a C1 _ 6 alkoxy group, a C1 - 6 alkylsulfonyl group (e.g., methylsulfonyl) and an aromatic heterocyclic group (e.g., furyl),
30    (b)   a  C6- 14   aryl  group  (e.g.,  phenyl),

(c)    a  C7- 13   aralkyl  group   (e.g.,  benzyl),

(d)    a  C1- 6   alkoxy  group,

(e)    a  C3- 10   cycloalkyl  group  (e.g.,   cyclopropyl},

(f)    a  C1- 6   alkylsulfonyl  group   (e.g.,  methylsulfonyl),

35    (g)   an  aromatic  heterocyclic  group   (e.g.,  triazolyl,

tetrazolyl),    and

(h) a non-aromatic heterocyclic group {e.g., tetrahydropyranyl);

(12)    a thiocarbamoyl group optionally mono- or di-substituted 5 by C1_ 6 alkyl group (s) optionally substituted by 1 to 3 halogen

atoms;

(13)    a sulfamoyl group optionally mono- or di-substituted by C1 - 6 alkyl group (s) optionally substituted by 1 to 3 halogen atoms;

w    (14) a carboxy group; {15) a hydroxy group;
(16)    a C1- 6 alkoxy group optionally substituted by 1 to 3 substi tuents selected from

(a)    a  halogen  atom,

15    (b)   a  carboxy  group,

(c)    a  C1 - 6   alkoxy  group,  and

{d)    a  C1- 6   alkoxy-carbonyl  group;

( 17) a C2- 6 alkenyloxy group (e.g., ethenyloxy) optionally substituted by 1 to 3 halogen atoms;

2'0 (18) a C3- 10 cycloalkyloxy group {e.g., cyclohexyloxy); (19) a C7- 13 aralkyloxy group (e.g., benzyloxy) optionally substituted by 1 to 3 halogen atoms;

(2 0) a c 6_14 aryloxy group (e.g., phenyloxy, naphthyloxy); (21) a c 1_ 6 alkyl-carbonyloxy group (e.g., acetyloxy, tert -
2'5    butylcarbonyloxy);

(22)    a  mercapto  group;

(23)    a C1- 6 alkylthio group (e.g., methylthio, ethylthio) optionally substituted by 1 to 3 substituents selected from
(a)    a  halogen  atom,

30    (b)   a  C6-14   aryl  group,  and

(c)    a  carboxy  group;

{24) a C6- 14 arylthio group (e.g., phenylthio, naphthylthio); {25) an aromatic heterocyclyl-thio group (e.g., tetrazolylthio) optionally substituted by 1 to 3 C1 _ 6 alkyl

35    groups;

(26)    a  sulfa  group;

(27)    a  cyano  group;

(28)    an  azido  group;

(29)    a  nitro  group;

s    (30)   a  nitroso  group;

(31)    a  halogen  atom;

(32)    a  C1- 6   alkylsulfinyl  group   (e.g.,  methylsulfinyl);

(33)    an  oxo  group;

(34)    a  C3- 10   cycloalkyl-C1- 6   alkyloxy  group   (e.g.,

10    cyclopropylmethyloxy);

(35)    a  C1 - 3   alkylenedioxy  group;

(36)    an aromatic heterocyclyl-carbonylthio group (e.g., indolylcarbonylthio) optionally substituted by 1 to 3 amino

groups    [the  amino  groups  are  each  optionally  mono-  or  di-

15    substituted by substituent (s) selected from a C1 - 6 alkyl group and an aromatic heterocyclyl-sulfonyl group (e.g., thienylsulfonyl)];

(37)    a  formyl  group;

(38)    an  aromatic  heterocyclyl-oxy  group   (e.g.,  pyrirnidyloxy,

20    pyrazinyloxy);

(39)    a  C1- 6   alkylsulfonyloxy  group   (e.g.,  methylsulfonyloxy);

(40) a C2_ 6 alkenyl-carbonyl group (e.g., vinylcarbonyl); ( 41) a non-aromatic heterocyclyl-carbonyloxy group (e.g.,

morpholinylcarbonyloxy)    optionally  substituted  by  1  to  3  C1 _ 6

25    alkyl  groups;

and  the  like  can  be  mentioned.

The C3- 10 cycloalkyl group, C3 - 10 cycloalkenyl group, C4_ 10 cycloalkadienyl group, C6-14 aryl group, C7- 13 aralkyl group, C8 _13 arylalkenyl group and C3 - 10 cycloalkyl-C1_ 6 alkyl group

30    exemplified  as  the  aforementioned  "hydrocarbon  group"

optionally have 1 to 3 substituents at substitutable positions. As such substituents, for example,
(1)    a  C3 - 10   cycloalkyl  group   (e.g.,  cyclopropyl,   cyclohexyl);

(2)    a  C6- 14   aryl  group  (e.g.,  phenyl,  naphthyl)   optionally

35    substituted  by  1  to  3  substituents  selected  from



(a)    a C1- 6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(b)    a  hydroxy  group,

(c)    a  C1 - 6   alkoxy  group,  and

(d)    a  halogen  atom;

(3)    aromatic heterocyclic group (e.g., thienyl, fury!, pyridyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, tetrazolyl, oxadiazolyl, pyrazinyl, quinolyl, indolyl) optionally substituted by 1 to 3 substituents selected from

10 (a) a C1_ 6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(b)    a  hydroxy  group,

(c)    a  C1- 6   alkoxy  group,  and

(d)    a  halogen  atom;

TI ~ ( 4) a non-aromatic heterocyclic group (e.g., tetrahydrofuryl, morpholinyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, dioxolyl, dioxolanyl, 1, 3-dihydro-2-benzofuranyl, thiazolidinyl, thiazolinyl) optionally substituted by 1 to substituents selected from

20 (a) a C1 - 6 alkyl group optionally substitUted by 1 to 3 halogen atoms,

(b)    a  hydroxy  group,

(c)    a  C1- 6   alkoxy  group,

(d)    a  C1- 6   alkyl-carbonyl  group,

25    (e)  a  C1- 6   alkylsulfonyl  group,

(f)    an  oxo  group,   and

(g)    a  halogen  atom;

(5)    an amino group optionally mono- or di-substituted by substituent (s) selected from
30 (a) a C1- 6 alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1- 6 alkylsulfonyl group (e.g., methylsulfonyl),

(b)    a  C1_ 6   alkyl-carbonyl  group,

(c)    a  C1- 6   alkoxy-carbonyl  group  optionally  substituted  by  1

35    to  3  C6- 14   aryl  groups   (e.g.,  phenyl),

(d)    a  C6_ 14   aryl-carbonyl  group   (e.g.,  benzoyl),

(e)    a C1_ 13 aralkyl-carbonyl group (e.g., benzylcarbonyl, phenethylcarbonyl),

(f)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by

substituent (s) selected from a C1- 6 alkyl group, a C6 - 14 aryl group (e.g., phenyl) and a C1 - 13 aralkyl group (e.g., benzyl),

(g)    a C1 - 6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, isopropylsulfonyl),
(h)    a  C6- 14   arylsulfonyl  group   (e.g.,  benzenesulfonyl,  1-

10    naphthalenesulfonyl, 2-naphthalenesulfonyl) optionally substituted by 1 to 3 C1 - 6 alkyl groups,

(i)    a  C1- 13   aralkylsulfonyl  group  (e.g.,  benzylsulfonyl)

(j)    a  C3- 10   cycloalkyl  group   (e.g.,   cyclohexyl)   optionally

substituted  by  1  to  3  substituents  selected  from  a  hydroxy

15    group  and  a  C1- 6   alkyl  group,

{k)    an  aromatic  heterocyclic  group   (e.g.,  triazolyl),  and

(1) a non-aromatic heterocyclic group (e.g., tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl, 1,1-dioxidotetrahydrothiopyranyl);

20    ( 6)   an  amidino  group;

(7)    a C1- 6 alkyl-carbonyl group optionally substituted by 1 to 3 halogen atoms;

(8) a C1 - 6 alkoxy-carbonyl group optionally substituted by 1 to 3 halogen atoms;

25 ( 9) an aromatic heterocyclyl-carbonyl group (e.g., thienylcarbonyl, indolylcarbonyl) optionally substituted by to 3 amino groups [the amino groups are each optionally mono-or di-substituted by substituent(s) selected from a C1_ 6 alkyl group and an aromatic heterocyclyl-sulfonyl group {e.g.,

30    thienylsulfonyl)];

(10)    a non-aromatic heterocyclyl-carbonyl group (e.g., piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-oxidothiornorpholinylcarbonyl, 1,1-dioxidothiomorpholinylcarbonyl, pyrrolidinylcarbonyl,

35    azetidinylcarbonyl)   optionally  substituted  by  1  to  3


substituents  selected  from

(a)    a  hydroxy  group,

(b)    a C1- 6 alkyl group optionally substituted by 1 to 3 hydroxy groups,

(c)    a  halogen  atom,  and

(d)    a  carboxy  group;

( 11) a C1- 6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl) optionally substituted by 1 to 3 halogen atoms; (12) a carbamoyl group optionally mono- or di-substituted by

10    substituent (s)   selected  from

(a)    a C1- 6 alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group, a C1 - 6 alkoxy

group, a C1- 6 alkylsulfonyl group (e.g., methylsulfonyl) and an aromatic heterocyclic group (e.g., fury!),
15    (b)   a  C6- 14   aryl  group   (e.g.,  phenyl},

(c)    a  C7 - 13   aralkyl  group  (e.g.,  benzyl),

(d)    a  C1- 6   alkoxy  group,

(e)    a  C3- 10   cycloalkyl  group   (e.g.,  cyclopropyl),

(f)    a  C1- 6   alkylsulfonyl  group  (e.g.,  methylsulfonyl),

20 (g) an aromatic heterocyclic group (e.g., triazolyl, tetrazolyl), and

(h) a non-aromatic heterocyclic group (e.g., tetrahydropyranyl);

(13)    a  thiocarbamoyl  group  optionally  mono-  or  di-substituted

25    by C1 - 6 alkyl group{s) optionally substituted by 1 to 3 halogen atoms;

(14)    a  sulfamoyl  group  optionally  mono-  or  di-substituted  by

C1- 6   alkyl  group{s)   optionally  substituted  by  1  to  3  halogen

atoms;

30    {15) a carboxy group; {16) a hydroxy group;
{17)   a  C1- 6   alkoxy  group  optionally  substituted  by  1  to  3

substituents  selected  from

(a)    a  halogen  atom,

35    (b)   a  carboxy  group,

19
 





(c)    a  C1 - 6   alkoxy  group,  and

(d)    a  C1 - 6   alkoxy-carbonyl  group;

(18)    a  C2- 6   alkenyloxy  group   (e.g.,   ethenyloxy)   optionally

substituted  by  1  to  3  halogen  atoms;

5    ( 19)   a  C3- 10   cycloalkyloxy  group   (e.g.,   cyclohexyloxy);

(20)    a C7- 13 aralkyloxy group (e.g., benzyloxy) optionally substituted by 1 to 3 halogen atoms;
(21)    a  C6- 14   aryloxy  group   (e.g.,  phenyloxy,  naphthyloxy);

(22)    a  C1 _6   alkyl-carbonyloxy  group   (e.g.,   acetyloxy,   tert-

10    butylcarbonyloxy);

(23)    a  mercapto  group;

(24)    a C1- 6 alkylthio group (e.g., methylthio, ethylthio) optionally substituted by 1 to 3 substituents selected from

(a)    a  halogen  atom,

15    (b)   a  C6- 14   aryl  group,  and

(c)    a  carboxy  group;

(25)    a C6- 14 arylthio group (e.g., phenylthio, naphthylthio); ( 2 6) an aromatic heterocyclyl-thio group (e.g.,
tetrazolylthio)    optionally  substituted  by  1  to  3  C1 - 6   alkyl

20    groups;

(27)    a  sulfa  group;

(28)    a  cyano  group;

(29)    an  azido  group;

(30)    a  nitro  group;

25    (31)   a  nitroso  group;

(33)    a  halogen  atom;

(33)    a  C1- 6   alkylsulfinyl  group  (e.g.,  methylsulfinyl);

(34)    an  oxo  group;

(35)    a  C3 - 10   cycloalkyl-C1- 6   alkyloxy  group   (e.g.,

30    cyclopropylmethyloxy);

(36)    a  C1- 3   alkylenedioxy  group;

(37)    an  aromatic  heterocyclyl-carbonylthio  group  (e.g.,

indolylcarbonylthio) optionally substituted by 1 to 3 amino groups [the amino groups are each optionally mono- or di-
35    substituted  by  substituent (s)   selected  from  a  C1 _6   alkyl  group

20
 





and an aromatic h~terocyclyl-sulfonyl group (e.g., thienylsulfonyl)]:

(38)    a  formyl  group;

(39)    an  aromatic  heterocyclyl-oxy  group   (e.g.,  pyrimidyloxy,

5    pyrazinyloxy);

(40)    a  C1 - 6   alkylsulfonyloxy  group  (e.g.,  methylsulfonyloxy);

(41) a C2- 6 alkenyl-carbonyl group (e.g., vinylcarbonyl); ( 42) a non-aromatic heterocyclyl-carbonyloxy group (e.g.,

morpholinylcarbonyloxy)    optionally  substituted  by  1  to  3  C1 _ 6

10    alkyl  groups;

(43)    a C1- 6 alkyl group optionally substituted by 1 to 3 substi tuents selected from
(a)    a  halogen  atom,

(b)    a  carboxy  group,

15    (c)   a  hydroxy  group,

(d) a C1- 6 alkoxy group optionally substituted by 1 to substituents selected from a carboxy group and a C1 _ 6 alkoxy-carbonyl group,

(e)    a  C1- 6   alkyl-carbonyl  group,

20    (f)   a  C1- 6   alkoxy-carbonyl  group,

(g)    a C1- 6 alkyl-carbonyloxy group (e.g., acetyloxy, tert - butylcarbonyloxy),

(h)    a carbamoyl group optionally mono- or di-substituted by substituent (s) selected from a C1 _6 alkyl, a C1 _ 6

alkylsulfonyl  group  and  an  amino  group,

( i) an aromatic heterocyclic group (e.g., thienyl, tetrazolyl, imidazolyl, fury!, pyridyl) optionally substituted by 1 to 3 C1 - 6 alkyl groups,

(j)    a  non-aromatic  heterocyclic  group   (e.g.,

30    tetrahydrofuranyl, piperidine, piperazinyl, morpholinyl, dihydrooxadiazolyl, hexahydropyrazinooxazinyl (e.g., hexahydropyrazino [2, 1-c] [1, 4] oxazinyl) ) optionally
substituted by 1 to 3 substituents selected from a C1_ 6 alkyl-carbonyl group and an oxo group,
35    (k)   an  amino  group  optionally  mono-  or  di-substituted  by  C1_

21
 





6 alkyl group(s) (the C1-6 alkyl group is optionally substituted by 1 to 3 substituents selected from a non-aromatic heterocyclic group (e.g., morpholinyl), a C1 _ 6 alkoxy group and a C1 -6 alkylsulfonyl group),

(l)    a C1- 6 alkylsulfonyl group optionally substituted by to 3 carboxy groups,

(m)    a C1 - 6 alkylthio group optionally substituted by 1 to 3 substituents selected from a carboxy group, a C1 _ 6 alkoxy-

carbonyl  group,  a  hydroxy  group  and  a  carbamoyl  group,

10 {n) a phosphene group optionally mono- or di-substituted by C1- 6 alkyl group (s),

(o)    a non-aromatic heterocyclyl-carbonyl group (e.g., morpholinylcarbonyl),

(p)    a  cyano  group,   and

15 (q) a C6-14 aryloxy group optionally substituted by 1 to substituents selected from a carboxy group and a C1_ 6 alkoxy-carbonyl group;

(44) a C2_ 6 alkenyl group (e.g., ethenyl, !-propenyl) optionally substituted by 1 to 3 substituents selected from

(a)    a  halogen  atom,

(b)    a  carboxy  group,

(c)    a  C1- 6   alkoxy-carbonyl  group,  and

(d)    a  carbamoyl  group;

( 45)   a  C7 - 13   aralkyl  group   (e.g.,  benzyl)   optionally  substituted

25    by  1  to  3  substituents  selected  from

(a)    a C1_ 6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(b)    a  hydroxy  group,

(c)    a  C1- 6   alkoxy  group,   and

30    (d)   a  halogen  atom;

and  the  like  can  be  mentioned.

As the "acyl group" for R6, R7 , R21 or R22 , for example, groups represented by the formulas: -CORa, -CO-ORa, -S02 Ra, - SORa, -CO-NRa' Rb' , -CS-NRa' Rb' and -SOz-NRa' Rb' wherein Ra is a

35    hydrogen  atom,   an  optionally  substituted  hydrocarbon  group  or


an optionally substituted heterocyclic group, and Ra' and Rb' are the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, or Ra' and Rb' form, together

s    with the adjacent nitrogen atom, an optionally substituted nitrogen-containing heterocycle, and the like can be mentioned.

As  the  "optionally  substituted  hydrocarbon  group"  for  Ra,

Ra' or Rb', those similar to the "optionally substituted hydrocarbon group" for R6, R7, R21 or R22 can be mentioned. As

10    the "optionally substituted heterocyclic group" for Ra, Ra' Rb', those similar to the below-mentioned "optionally substituted heterocyclic group" for R3 can be mentioned.

As  the  "nitrogen-containing  heterocycle"  of  the

"optionally  substituted  nitrogen-containing  heterocycle"

15    formed by Ra' and Rb' together with the adjacent nitrogen atom, for example, a 5- to 7-mernbered nitrogen-containing

heterocycle containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom and optionally further containing one or two heteroatoms selected from an

20 oxygen atom, a sulfur atom and a nitrogen atom can be mentioned. As preferable examples of the nitrogen-containing heterocycle, pyrrolidine, irnidazolidine, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, oxopiperazine and the like can be mentioned.

25 The nitrogen-containing heterocycle optionally has 1 to (preferably 1 or 2) substituents at substitutable positions. As such substituents, those exemplified as the substituents

which the C3- 10 cycloalkyl group and the like exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon
30 group" for R6, R7, R21 or R22 optionally has, can be mentioned. As preferable examples of the "acyl group",

(1)    a  formyl  group;

(2)    a  carboxy  group;

(3)    a  carbamoyl  group;

35    (4)  a  C1 - 6   alkyl-carbonyl  group;


(5) a C1- 6 alkoxy-carbonyl group optionally substituted by 1 to 3 substituents selected from

(a)    a  carboxy  group,

(b)    a  carbamoyl  group,

(c)    a  thiocarbamoyl  group,

(d)    a  C1- 6   alkoxy-carbonyl  group,   and

(e)    a  C1- 6   alkyl-carbonyloxy  group

(e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl; carboxyrnethoxycarbonyl, carboxyethoxycarbonyl,

10 carboxybutoxycarbonyl; carbarnoylmethoxycarbonyl; thiocarbamoy lmethoxycarbon y 1; ethoxycarbony lmethoxycarbon y 1, ethoxycarbonyl ethoxycarbon yl, methoxycarbony lbutoxycarbon y 1, ethoxycarbonylbutoxycarbonyl; tert-butylcarbonyloxymethoxycarbonyl);

15    (6)   a  C3 - 10   cycloalkyl-carbonyl  group   (e.g.,   cyclopentylcarbonyl,

cyclohexylcarbonyl);

(7) a C6- 14 aryl-carbonyl group (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) optionally substituted by 1 to 3 substituents selected from

20    (a) a halogen atom, {b) a cyano group,
(c)    a C1- 6 alkyl group optionally substituted by 1 to 3 halogen atoms,

(d)    a  C1- 6   alkoxy  group,

25    {e)   a  carboxy  group,

(f)    a  C1- 6   alkoxy-carbonyl  group,   and

(g)    a  carbamoyl  group;

( 8) a C6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl) optionally substituted by 1 to 3

30    substi tuents  selected  from

(a)    a  carboxy  group,

(b)    a  C1 - 6   alkoxy-carbonyl  group,  and

(c)    a  carbamoyl  group;

(9)    a  C7- 13   aralkyloxy-carbonyl  group  optionally  substituted  by

35    1  to  3  substituents  selected  from


(a)    a  carboxy  group,

(b)    a  carbamoyl  group,

(c)    a  thiocarbamoyl  group,

(d)    a  C1 - 6   alkoxy-carbonyl  group,

(e)    a  halogen  atom,

(f)    a  cyano  group,

(g)    a  nitro  group,

(h)    a  C1- 6   alkoxy  group,

(i)    a  C1- 6   alkylsulfonyl  group,   and

10    (j)   a  C1- 6   alkyl  group

(e.g., benzyloxycarbonyl, phenethyloxycarbonyl; carboxybenzyloxycarbonyl; methoxycarbonylbenzyloxycarbonyl; biphenylylmethoxycarbonyl);

(10)    a  carbamoyl  group  mono-  or  di-substituted  by  C1- 6   alkyl

15    group ( s) optional! y substituted by 1 to 3 substi tuents selected from a halogen atom and a C1 - 6 alkoxy group

(e.g.,  methylcarbamoyl,  ethylcarbamoyl,  dimethylcarbamoyl,

diethylcarbamoyl,    ethylmethylcarbamoyl,  propylcarbamoyl,

isopropylcarbamoyl,    butylcarbamoyl,   isobutylcarbamoyl,

20    trifluoroethylcarbamoyl,  N-methoxyethyl-N-methylcarbamoyl);

(11)    a C1_ 6 alkylsulfonyl group optionally substituted by 1 to substi tuents selected from

(a)    a  carboxy  group,

(b)    a  carbamoyl  group,   and

25    (c)   a  C1 - 6   alkoxy-carbonyl  group

(e.g.,  methylsulfonyl,   carboxymethylsulfonyl);

(12)    a  C1 - 6   alkylsulfinyl  group  (e.g.,  methylsulfinyl);

(13)    a  thiocarbamoyl  group;

(14)    a  C7 - 13   aralkyl-carbonyl  group  (e.g.,  benzylcarbonyl,

30    phenethylcarbonyl);

(15)    an aromatic heterocyclyl-carbonyl group (e.g., furylcarbonyl, thienylcarbonyl, thiazolylcarbonyl,

pyrazolylcarbonyl,    pyridylcarbonyl,  pyrazinylcarbonyl,

benzofurylcarbonyl,    benzothienylcarbonyl,

35    quinoxalinylcarbonyl)   optionally  substituted  by  1  to  3


substi tuents  selected  from

(a)    a  C1- 6   alkyl  group,

(b)    a  C6-14   aryl  group,

(c)    a  C1-13   aralkyl  group,

(d)    a  C 1_ 6   alkoxy  group,

(e)    a  carboxy  group,

(f)    a  C 1- 6   alkoxy-carbonyl  group,  and

(g)    a  carbamoyl  group;

(16)    a  non-aromatic  heterocyclyl-carbonyl  group   (e.g.,

10    tetrahydrofurylcarbonyl, morpholinylcarbonyl, thiorn.orpholinylcarbonyl, piperidinylcarbonyl,

pyrrolidinylcarbonyl, piperazinylcarbonyl, dioxolylcarbonyl, dioxolanylcarbonyl, 1, 3-dihydro-2-benzofuranylcarbonyl, thiazolidinylcarbonyl) optionally substituted by 1 to 3

15    substituents  selected  from

(a)    a C1- 6 alkyl group optionally substituted by 1 to halogen atoms,

(b)    a  hydroxy  group,

(c)    a  C1- 6   alkoxy  group,  and

20 (d) a halogen atom; {17) a sulfamoyl group;
(18) a sulfamoyl group mono- or di-substituted by C1 - 6 alkyl group(s) optionally substituted by 1 to 3 substituents selected from a halogen atom and a C1 _ 6 alkoxy group

25 (e.g., methylsulfamoyl, ethylsulfarnoyl, dimethylsulfamoyl); and the like can be mentioned.

When R6 and R7 are independent, R6 is preferably an optionally substituted C1- 6 alkyl group, a cyano group or acyl group, more preferably a C1_6 alkyl group substituted by

30 optionally substituted heterocyclic group. As preferable specific examples for R6 ,
(1) a C1- 6 alkyl group {preferably methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents selected from

{a)    a  non-aromatic  heterocyclic  group  (preferably

35    piperidinyl,  pyrrolidinyl,  morpholinyl,  piperazinyl)



optionally  substituted  by  1  to  3  substituents  selected  from

(i)    a  hydroxy  group,

{ii)    a  C1 - 6   alkyl-carbonyl  group   (preferably  acetyl),
{iii)    a  C1~ 6 alkylsulfonyl  group   (preferably

methylsulfonyl),    and

(iv)    a  halogen  atom  (preferably  fluorine  atom),

(b)    an  amino  group,

(c)    a  hydroxy  group,  and

(d)    a  C1 - 6   alkoxy  group  (preferably  methoxy);

10    (2)   a  cyano  group;

(3)    a  carboxy  group;

(4)    a  C1- 6   alkoxy-carbonyl  group  {preferably  methoxycarbonyl);

(5)    a  carbamoyl  group;  and

(6)    a  non-aromatic  heterocyclyl-carbonyl  group  (preferably

15    pyrrolidinylcarbonyl);

[preferably a C1 - 6 alkyl group (preferably methyl, ethyl, isopropyl) substituted by 1 to 3 substituents selected from

(a) a non-aromatic heterocyclic group (preferably piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl)

20    optionally  substituted  by  1  to  3  substituents  selected  from

(i)    a  hydroxy  group,

(ii)    a  C1 _ 6   alkyl-carbonyl  group  (preferably  acetyl),

(iii)    a  C1 _ 6   alkylsulfonyl  group  (preferably

methylsulfonyl),    and

25 (iv) a halogen atom (preferably fluorine atom) J can be mentioned.

As  another  preferable  specific  examples  for  R6 ,

(1) a C1- 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents

30    selected  from

(a)    a  heterocyclic  group   (preferably  piperidinyl,

pyrrolidinyl,  morpholinyl,  piperazinyl,  thiomorpholinyl,  1-

oxidothiomorpholinyl,    1, 1-dioxidothiomorpholinyl,

pyrazolinyl,    pyrazolidinyl,   azetidinyl,   imidazolyl,

35    triazolyl)  optionally  substituted  by  l   to  3  substituents

27
 





selected  from

(i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl-carbonyl  group  (preferably  acetyl),

(iii)    a C1- 6 alkylsulfonyl group (preferably methylsulfonyl),
(iv)    a  halogen  atom  (preferably  fluorine  atom),

(v)    an  oxo  group,

(vi)    a C1- 6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 hydroxy groups, and

10 (vii) a C1- 3 alkylenedioxy group (preferably ethy1enedioxy),

(b) an amino group optionally mono- or di-substituted by substituent (s) selected from
(i)    a  C1 - 6   alkyl  group  (preferably  methyl,  ethyl,

15    isobutyl) optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1 _ 6 alkylsulfonyl group {preferably methylsulfonyl),

(ii)    a  C1- 6   alkyl-carbonyl  group  (preferably  acetyl),

(iii)    a  C1- 6   alkoxy-carbonyl  group   (preferably

20    methoxycarbonyl) optionally substituted by 1 to 3 C6 - 14 aryl groups (preferably phenyl),
(iv)    a  C3 - 10   cycloalkyl  group   (preferably  cyclohexyl)

optionally  substituted  by  1  to  3  substituents  selected

from  a  hydroxy  group  and  a  C1 - 6   alkyl  group  (preferably

25    methyl) 1

(v)    an aromatic heterocyclic group (preferably triazolyl), and

(vi)    a non-aromatic heterocyclic group (preferably tetrahydrothiopyranyl, 1-oxidotetrahydrothiopyranyl,

30    1 1 1-dioxidotetrahydrothiopyrany1),

(c)    a  hydroxy  group,

{d)    a  C1- 6   alkoxy  group  {preferably  methoxy) 1

(e)    a  C1 - 6   alkylsulfonyloxy  group  (preferably

methylsulfonyloxy),

35    (f)   a  C1_ 6   alkyl-carbonyl  group  (preferably  acetyl},

(g)    a  C2_ 6   alkenyl-carbonyl  group   (preferably  vinylcarbonyl),

(h)    a  C1_ 6   alkoxy-carbonyl  group   (preferably  ethoxycarbonyl),

(i)    a  carboxy  group,

(j)    a non-aromatic heterocyclyl-carbonyl group (preferably piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-oxidothiomorpholinylcarbonyl, 1,1-

dioxidothiomorpholin y lcarbony1,  pyr rolidin y l carbonyl,

azetidinylcarbonyl}    optionally  substituted  by  1  to  3

10    substituents  selected  from

(i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl  group   (preferably  methyl,   ethyl)

optionally  substituted  by  1  to  3  hydroxy  groups,

(iii)    a  halogen  atom  (preferably  fluorine  atom),   and

15    (iv)   a  carboxy  group,

(k)    a  non-aromatic  heterocyclyl-carbonyloxy  group

(preferably  morpholinylcarbonyloxy)   optionally  substituted

by  1  to  3  C1- 6  alkyl  groups   (preferably  methyl),

(1)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by

20    substituent (s)   selected  from

(i)    a C1- 6 alkyl group (preferably methyl, ethyl} optionally substituted by 1 to 3 substituents selected
from  a  hydroxy  group,  a  C1 - 6   alkoxy  group   (preferably

methoxy)    and  a  C1- 6   alkylsulfonyl  group   (preferably

25    methylsulfonyl),

(ii)    a  C1- 6   alkoxy  group   (preferably  methoxy),

(iii)    a  C3- 10   cycloalkyl  group   (preferably  cyclopropyl),

(iv)    a C1 - 6 alkylsulfonyl group (preferably methylsulfonyl),

30    (v}   an  aromatic  heterocyclic  group   (preferably  triazolyl,

tetrazolyl),    and

(vi)    a  non-aromatic  heterocyclic  group   (preferably

tetrahydropyranyl),

(m)    a  C1- 6  alkylthio  group   (preferably  methylthio)

35    optionally  substituted  by  1  to  3  carboxy  groups,   and

(n)    a  formyl  group;

(2)    a  cyano  group;

(3)    a  carboxy  group;

(4)    a  C1_ 6  alkoxy-carbonyl  group   (preferably  methoxycarbonyl);

s    (5) a carbamoyl group optionally mono- or di-substituted by c 1 _ 6 alkyl group (s) (preferably ethyl); and

(6)    a  non-aromatic  heterocyclyl-carbonyl  group  (preferably

pyrrolidinylcarbonyl,    morpholinylcarbonyl,

piperazinylcarbonyl)    optionally  substituted  by  1  to  3  C1 _ 6   alkyl

10    groups   (preferably  methyl);

[preferably a C1 - 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) substituted by 1 to 3 substituents selected from

(a)    a  heterocyclic  group  (preferably  piperidinyl,

15    pyrrolidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1, 1-dioxidothiomorpholinyl, pyrazolinyl, pyrazolidinyl, azetidinyl, imidazolyl,

triazolyl)    optionally  substituted  by  1  to  3  substituents

selected  from

20    (i)   a  hydroxy  group,

(ii)    a  C1- 6   alkyl-carbonyl  group  (preferably  acetyl),

(iii)    a C1 _ 6 alkylsulfonyl group {preferably methylsulfonyl),

(iv)    a  halogen  atom  (preferably  fluorine  atom),

25    (v)   an  oxo  group,

(vi)    a C1 - 6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 hydroxy groups, and
(vii)    a C1 - 3 alkylenedioxy group (preferably ethylenedioxy))

30    can  be  mentioned.

When R6 and R7 are independent, R7 is preferably a hydrogen atom or an optionally substituted C1 - 6 alkyl group, more preferably a hydrogen atom.

As  preferable  specific  examples  for  R7 ,

35    (1)   a  hydrogen  atom;  and


(2) a C1 - 6 alkyl group (preferably methyl); can be mentioned.
When R6 and R7 in combination form an optionally substituted ring, as the "ringu of the "optionally substituted
5    ring", for example, a C3 - 10 cycloalkane, a C3_ 10 cycloalkene, a C3 _10 cycloalkadiene, a monocyclic non-aromatic heterocycle and the like can be mentioned.

As the C3-1o cycloalkane, C3 - 10 cycloalkene and C4- 10 cycloalkadiene, rings corresponding to the C3 _ 10 cycloalkyl

10    group, C3- 10 cycloalkenyl group and C4- 10 cycloalkadienyl group exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R6 , R7 , R21 or R22 can be mentioned. As the monocyclic non-aromatic heterocycle, a ring

corresponding  to  the  monocyclic  non-aromatic  heterocyclic

15    group exemplified as the below-mentioned "optionally substituted heterocyclic group" for R3 , can be mentioned.

The  "ring"  of  the  "optionally  substituted  ring"

optionally  has  1  to  3  substituents  at  substitutable  positions.

As  such  substituents,  those  exemplified  as  the  substituents

20    which the C3 - 10 cycloalkyl group and the like exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R6 , R7 , R21 or R22 optionally has, can be mentioned.
When  R6   and  R7   in  combination  form  an  optionally

substituted  ring,   the  "optionally  substituted  ring"  is

25    preferably an optionally substituted mono cyclic non-aromatic heterocycle (preferably piperidine, tetrahydropyran, 1-oxidotetrahydrothiopyran) or an optionally substituted C3 - 10 cycloalkane (preferably cyclohexane), more preferably an

optionally  substituted  monocyclic  non-aromatic  heterocycle

JO (preferably piperidine, tetrahydropyran, 1-oxidotetrahydrothiopyran) .

As preferable specific examples, a monocyclic non-aromatic heterocycle (preferably piperidine, tetrahydropyran) optionally substituted by 1 to 3 substituents selected from

35    (a)   a  C1- 6   alkyl  group   (preferably  methyl,  ethyl)   optionally

substituted by aromatic heterocyclic group(s) (preferably imidazolyl) optionally substituted by 1 to 3 C1~6 alkyl groups (preferably methyl),

(b)    a  C7~13 aralkyl  group  (preferably  benzyl),

(c)    a  C1~6 alkyl-carbonyl  group   (preferably  acetyl) 1

(d)    a  C1~6 alkylsulfonyl  group   (preferably  methyl.sulfonyl) 1

and

(e)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by
C1~6 alkyl  group ( s)   (preferably  methyl);

10    can  be  mentioned.

As  another  preferable  specific  examples,

(1) a monocyclic non-aromatic heterocycle (preferably piperidine 1 tetrahydropyran 1 1-oxidotetrahydrothiopyran) optionally substituted by 1 to 3 substituents selected from

15 (a) a C1~6 alkyl group (preferably methyl, ethyl, isobutyl) optionally substituted by 1 to 3 substituents .selected from

(i) an aromatic heterocyclic group (preferably imidazolyl, fury!, pyridyl) optionally substituted by to 3 C1~6 alkyl groups (preferably methyl),

20    (ii)   a  cyano  group,

(iii)    a  hydroxy  group,

(iv)    a  carboxy  group,

(v)    a  C1~6 alkoxy  group   (preferably  methoxy),
(vi)    a  C1~6 alkyl-carbonyl  group   (preferably  acetyl),

25 (vii) a C1_ 6 alkoxy-carbonyl group (preferably methoxycarbonyl) , and

(viii) a carbamoyl group optionally mono- or di-substituted by C1 - 6 alkyl group(s) (preferably ethyl) 1
(b)    a  C1-13   aralkyl  group  (preferably  benzyl) 1

30    (c)   a  C1- 6   alkyl-carbonyl  group   (preferably  acetyl),

(d)    a  C1 - 6   alkyl.sulfonyl  group   (preferably  methylsulfonyl) 1

(e)    a carbamoyl group optionally mono- or di-substituted by C1- 6 alkyl group {s) (preferably methyl) 1 and

(f)    a  non-aromatic  heterocyclic  group   (preferably

35    tetrahydropyranyl);  and

R7 ,    R21   or  R22   can  be  mentioned.

The "C3- 10 cycloalkyl group" optionally has 1 to 3 substituents at substitutable positions. As such substituents, those exemplified as the substituents which the C3 - 10 cycloalkyl

5    group  and  the  like  exemplified  as  the  "hydrocarbon  group"  of

the "optionally substituted hydrocarbon group" for R6 , R7 , R21 or R22 optionally has, can be mentioned.
When Rq and R5 are independent, R4 and R5 are preferably each independently

(1)    a C1_ 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl) optionally substituted by 1 to 3 substi tuents selected from

(a)    a  C1- 6   alkoxy  group  (preferably  methoxy,   ethoxy),

(b)    a  C1- 6   alkylsulfonyl  group  (preferably  methylsulfonyl,

15    ethylsulfonyl),

(c)    a C1- 6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl), and

(d)    an  aromatic  heterocyclic  group  (preferably  pyridyl);

(2)    a  C3- 10   cycloalkyl  group  (preferably  cyclopropyl).

20 When R4 and R5 in combination form an optionally substituted ring, as the "ring" of the "optionally substituted ring", an optionally substituted nitrogen-containing non-aromatic heterocycle can be mentioned. As the "nitrogen-containing non-aromatic heterocycle" of the "optionally

25    substituted nitrogen-containing non-aromatic heterocycle", for example, a monocyclic nitrogen-containing non-aromatic heterocycle (the ring should not be morpholine), a fused nitrogen-containing non-aromatic heterocycle, a nitrogen-

containing  spiro  ring  and  the  like  can  be  mentioned.

30 As the "monocyclic nitrogen-containing non-aromatic heterocycle", for example, a 5- to 7-membered monocyclic nitrogen-containing non-aromatic heterocycle (the ring should not be morpholine) containing, as a ring-constituting atom besides carbon atoms, at least one nitrogen atom and

35    optionally  further  containing  1  to  3  heteroatorns  selected  from

an oxygen atom, a sulfur atom and a nitrogen atom can be mentioned. As preferable specific examples of the 5- to 7-mernbered monocyclic nitrogen-containing non-aromatic heterocycle, pyrrolidine, oxopyrrolidine, dioxopyrrolidine,

5    piperidine, thiomorpholine, 1, 1-dioxidothiomorpholine, piperazine, oxopiperazine and the like can be mentioned.

As  the  "fused  nitrogen-containing  non-aromatic

heterocycle",    for  example,   a  ring  wherein  the  above-mentioned

5-  to  7-mernbered  monocyclic  nitrogen-containing  non-aromatic

10    heterocycle and 1 or 2 rings selected from a 5 or 6-mernbered aromatic heterocycle, a 5 or 6-mernbered non-aromatic

heterocycle and a benzene ring are condensed, and a ring wherein the above-mentioned ring is partially saturated,

be  mentioned.   As  the  5  or  6-mernbered  aromatic  heterocycle  and

15    5 or 6-mernbered non-aromatic heterocycle, for example, a ring corresponding to a 5- or 6-mernbered ring group, from among the aromatic heterocyclic group and non-aromatic heterocyclic group exemplified as the "heterocyclic group" of the below-

mentioned  "optionally  substituted  heterocyclic  group"  for  R3 ,

20    can  be  mentioned.

As preferable specific examples of the fused nitrogen-containing non-aromatic heterocycle, tetrahydropyrrolo [3, 4-c] pyrrole-1, 3 (2H, 3aH) -diane, hexahydropyrazino [2, 1-

c]  [1, 4] oxazin-4 (3H) -one,  hexahydro [ 1, 3] oxazolo [3, 4-a] pyrazin-

25    3-one, 5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [ 4, 3-a] pyrazine and the like can be mentioned.

As  the  "nitrogen-containing  spiro  heterocycle~<,  for

example, a ring formed by the above-mentioned 5- to 7-mernbered monocyclic nitrogen-containing non-aromatic heterocycle and 1
30    or 2 rings selected from a C3 - 10 cycloalkane, a C3 _ 10 cycloalkene, a C4 _10 cycloalkadiene and a 5 or 6-mernbered non-aromatic heterocycle can be mentioned.

As the C3 - 10 cycloalkane, C3 - 10 cycloalkene and C4 _ 10 cycloalkadiene, a ring corresponding to the C3 _10 cycloalkyl

35    group,  C3 - 10   cycloalkenyl  group  and  C4- 10   cycloalkadienyll   group

exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R6 , R7 , R21 or R22 can be mentioned. As the 5 or 6-membered non-aromatic heterocycle, a ring corresponding to a 5- or 6-membered ring group, from

5    among the monocyclic non-aromatic heterocyclic group exemplified as the "heterocyclic group" of the below-mentioned "optionally substituted heterocyclic group" for R3 , can be

mentioned.

As  preferable  specific  examples  of  the  nitrogen-

10    containing spiro heterocycle, 1-oxa-3, 8-diazaspiro [ 4. 5] decan-2-one and the like can be mentioned.

The "ringu of the "optionally substituted ring" optionally has 1 to 3 substituents at substitutable positions. As such substituents, those exemplified as the substituents

15    which the C3 - 10 cycloalkyl group and the like exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon
group" for R6 , R7 , R21 or R22 optionally has, can be mentioned. When R4 and R5 in combination form an optionally
substituted  ring,   the  "optionally  substituted  ring"  is

20    preferably an "optionally substituted nitrogen-containing non-aromatic heterocycle (the ring should not be morpholine) ", more preferably a nitrogen-containing non-aromatic heterocycle (the ring should not be morpholine)

[preferably  a  monocyclic  nitrogen-containing  non-aromatic

25 heterocycle (the ring should not be morpholine) (preferably pyrrolidine, oxopyrrolidine, piperidine, thiomorpholine, 1,1-dioxidothiornorpholine, piperazine, oxopiperazine);

a fused nitrogen-containing non-aromatic heterocycle (preferably tetrahydropyrrolo [3, 4-c]pyrrole-1, 3 (2H, 3aH) -diane,

30    hexahydropyrazino [2, 1-c] [1, 4] oxazin-4 (3H) -one, hexahydro [1, 3] oxazolo [3, 4-a] pyrazin-3-one, 5, 6, 7, 8-tetrahydro [1, 2, 4] triazolo [ 4, 3-a] pyrazine); or

a nitrogen-containing spiro heterocycle (preferably 1-oxa-3,8-diazaspiro [4 .5]decan-2-one)] optionally substituted by 1 to 3

35    substi tuents  selected  from

(1) a C1_ 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl) optionally substituted by 1 to 3 substituents selected from

(a)    a  halogen  atom  (preferably  fluorine  atom),

(b)    a  carboxy  group,

(c)    a  hydroxy  group,

(d)    a  C1- 6   alkoxy  group   (preferably  methoxy,  ethoxy),

(e)    a C1- 6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl),

10 (f) a carbamoyl group optionally mono- or di-substituted by C1_ 6 alkyl group (s) (preferably methyl), and
(g) a non-aromatic heterocyclic group (preferably tetrahydrofuranyl);

(2)    an  aromatic  heterocyclic  group   (preferably  pyridyl,

15    pyrimidinyl)  optionally  substituted  by  1  to  3  C1- 6   alkyl  groups;

(3)    an  amino  group  optionally  mono-  or  di-substituted  by  C1- 6

alkyl-carbonyl  group (s)   (preferably  acetylamino) ;

(4)    a  C1 - 6   alkyl-carbonyl  group  (preferably  acetyl);

(5)    a  C1_ 6   alkoxy-carbonyl  group   (preferably  methoxycarbonyl,

20    ethoxycarbonyl);

(6)    a non-aromatic heterocyclyl-carbonyl group (preferably pyrrolidinylcarbonyl);

(7)    a C1- 6 alkylsulfonyl group (preferably methylsulfonyl, ethylsulfonyl);

25    (8)  a  carbamoyl  group;

(9)    a  hydroxy  group;  and

(10)    an aromatic heterocyclyl-oxy group (preferably pyrirnidyloxy, pyrazinyloxy) .
Preferably,    R4   and  R5   in  combination  form  an  optionally

30    substituted  ring  (the  ring  should  not  be  morpholine).

W is 0 or NR8 wherein R8 is a hydrogen atom, an optionally substituted C1- 6 alkyl group or an optionally substituted C3 - 10 cycloalkyl group.

35    W is  preferably  NR8   wherein  R8   is  defined  above.
The "C 1 - 6 alkyl group" of the "optionally substituted C1 _ 6 alkyl group" for R8 optionally has 1 to 3 substituents at substitutable positions. As such substituents, those exemplified as the substituents which the C1 - 10 alkyl group and

5    the like exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R6 , R7 , R21 or R22 optionally has, can be mentioned.

As  the  "optionally  substituted  C3 _10   cycloalkyl"  for  R8 ,

those  similar  to  the  "optionally  substituted  C3 - 10   cycloalkyl"

10    for  R4   or  R5   can  be  mentioned.

As  preferable  specific  examples  for  R8

(1)    a  hydrogen  atom;  and

(2)    a  C1_ 6   alkyl  group   (preferably  methyl,   ethyl,  propyl,

isopropyl)    optionally  substituted  by  1  to  3  substituents

15    selected  from

(a)    a  C3 - 10   cycloalkyl  group   (preferably  cyclopropyl),  and

(b)    a  C1- 6   alkoxy  group  (preferably  methoxy,  ethoxy);

can  be  mentioned.

As  another  preferable  specific  examples  for  R8

20    ( 1)   a  hydrogen  atom;  and

(2)    a C1_ 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substi tuents selected from

(a)    a  C3_ 10   cycloalkyl  group   (preferably  cyclopropyl),

25    (b) a C1- 6 alkoxy group (preferably methoxy, ethoxy), {c) a halogen atom (preferably fluorine atom),

(d)    a  cyano  group,

(e)    a  hydroxy  group,

(f)    a  carboxy  group,

30    (g)   a  carbamoyl  group,  and

(h)    a C1_ 6 alkoxy-carbonyl group (preferably ethoxycarbonyl);

can  be  mentioned.

35    R3   is  an  optionally  substituted  heterocyclic  group  or  an

optionally  substituted  C6- 14   aryl  group.

As the "heterocyclic group" of the "optionally substituted heterocyclic group" for R3 , an aromatic heterocyclic group and a non-aromatic heterocyclic group

5    be  mentioned.

As used herein, as the aromatic heterocyclic group, for example, a 4- to 7-membered (preferably 5- or 6-membered) monocyclic aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms

10    selected  from  an  oxygen  atom,  a  sulfur  atom  and  a  nitrogen

atom, and a fused aromatic heterocyclic group can be mentioned. As the fused aromatic heterocyclic group, for example 1 a group derived from a fused ring wherein a ring corresponding to the

4-  to  7-membered  monocyclic  aromatic  heterocyclic  group  and  1

15    or 2 rings selected from a 5- or 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole 1 imidazole, pyrazole, pyrazine, pyridine, pyrimidine), a 5-

membered  aromatic  heterocycle  containing  one  sulfur  atom   (e.g.,

thiophene)    and  a  benzene  ring  are  fused,   and  the  like  can  be

20    mentioned.

As preferable examples of the aromatic heterocyclic group, monocyclic aromatic heterocyclic groups such as furyl (e.g.,

2-furyl 1 3-furyl), thienyl (e.g. 1 2-thienyl, 3-thienyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl

25 (e.g. 1 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrazinyl (e.g., 2-pyrazinyl), pyrrolyl (e.g., 1-pyrrolyl 1 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g. 1 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-

30    pyrazolyl, 4-pyrazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (e.g. 1 4-isothiazolyl) 1 oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,2,4-

oxadiazol-5-yl,  1,3,4-oxadiazol-2-yl),  thiadiazolyl   (e.g.,

35    1,3,4-thiadiazol-2-yl 1    1,2 1  4-thiadiazol-3-yl,  1,2,4-
thiadiazol-5-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl), tetrazolyl (e.g., tetrazol-1-yl, tetrazol-5-yl), triazinyl (e.g., 1,2,4-triazin-1-yl, 1,2,4-triazin-3-yl) and

5    the  like;

fused heterocyclic group such as quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl, 6-quinolyl), isoquinolyl (e.g., 3-isoquinolyl), quinazolyl (e.g., 2-quinazolyl, 4-quinazolyl),

quinoxalyl    (e.g.,   2-quinoxalyl,   6-quinoxalyl},  benzofuryl

10 (e.g., 2-benzofuryl, 3-benzofuryl), benzothienyl (e.g., 2-benzothienyl, 3-benzothienyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzisoxazolyl (e.g., 7-benzisoxazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzimidazolyl (e.g., benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl),

15 benzotriazolyl (e.g., 1H-1, 2, 3-benzotriazol-5-yl) , indolyl (e.g., indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl),

indazolyl (e.g., 1H-indazol-3-yl}, pyrrolopyrazinyl (e.g., 1H-pyrrolo [2, 3-b] pyrazin-2-yl, 1H-pyrrolo [2, 3-b] pyrazin-6-yl), imidazopyridinyl (e.g., 1H-imidazo[4,5-b]pyridin-2-yl, 1H-

20    imidazo [ 4, 5-c] pyridin-2-yl, 2H-imidazo [1, 2-a] pyridin-3-yl), imidazopyrazinyl (e.g., 1H-imidazo [ 4, 5-b] pyrazin-2-yl), imidazothiazolyl (e.g., imidazo [2, 1-b] thiazol-5-

yl) pyrazolopyridinyl   (e.g.,  1H-pyrazolo [ 4, 3-c] pyridin-3-yl),

pyrazolothienyl    (e.g.,   2H-pyrazolo [3, 4-b] thiophen-2-yl) ,

25    pyrazolotriazinyl (e.g., pyrazolo [5, 1-c] [1, 2, 4] triazin-3-yl) and the like;

and  the  like  can  be  mentioned.

As the non-aromatic heterocyclic group, for example, a 4-to 7-membered (preferably 5- or 6-membered) monocyclic non-

JO    aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atoms, 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and a fused non-aromatic heterocyclic group can be mentioned. As the fused non-aromatic heterocyclic group, for example, a group derived

35    from  a  fused  ring  wherein  a  ring  corresponding  to  the  4-  to  7-


membered monocyclic non-aromatic heterocyclic group and 1 or 2 rings selected from a 5- or 6-membered aromatic or non-aromatic heterocycle containing 1 or 2 nitrogen atoms (e.g., pyrrole, imidazole, pyrazole, pyrazine, pyridine, pyrimidine,

5 pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine}, a 5-membered aromatic or non-aromatic heterocycle containing one sulfur atom (e.g., thiophene, tetrahydrothiophene) and a benzene ring are fused, a group wherein the above-mentioned group is partially saturated, and

10    the  like  can  be  mentioned.

As  preferable  examples  of  the  non-aromatic  heterocyclic

group,

monocyclic non-aromatic heterocyclic groups such as tetrahydrofuranyl (e.g., 2-tetrahydrofuranyl), pyrrolidinyl

15 (e.g., 1-pyrrolidinyl), piperidinyl (e.g., piperidine, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl (e.g., morpholino), thiomorpholinyl (e.g., thiomorpholino), piperazinyl (e.g., 1-piperazinyl, 2-piperazinyl, 3-

piperazinyl),    hexamethyleniminyl   (e.g.,   hexamethylenimin-1-yl},

20    oxazolidinyl (e.g., oxazolidin-2-yl), thiazolidinyl (e.g., thiazolidin-2-yl), imidazolidinyl (e.g., imidazolidin-2-yl, imidazolidin-3-yl), oxazolinyl (e.g., oxazolin-2-yl),

thiazolinyl (e.g., thiazolin-2-yl), imidazolinyl (e.g., imidazolin-2-yl, imidazolin-3-yl), dioxolyl (e.g., 1, 3-dioxol-

25    4-yl), dioxolanyl (e.g., 1,3-dioxolan-4-yl), dihydrooxadiazolyl {e.g., 4, 5-dihydro-1, 2, 4-oxadiazol-3-yl}, thioxooxazolidinyl (e.g., 2-thioxo-1, 3-oxazolidin-5-yl),

pyranyl    {e.g.,   4-pyranyl),  tetrahydropyranyl  {e.g.,   4-

tetrahydropyranyl},    thiopyranyl  {e.g.,   4-thiopyranyl},

30    tetrahydrothiopyranyl {e.g., 4-tetrahydrothiopyranyl) , 1-oxidotetrahydrothiopyranyl (e.g., 1-oxidotetrahydrothiopyran-4-yl), 1, 1-dioxidotetrahydrothiopyranyl {e.g., 1, 1-

dioxidotetrahydrothiopyran-4-yl), pyrazolidinyl {e.g., pyrazolidin-1-yl), tetrahydropyrimidinyl, dioxanyl (e.g., 1, 3-

35    dioxan-2-yl,   1, 3-dioxan-4-yl,  1, 3-dioxan-5-yl,  1, 4-dioxan-2-


yl),    dioxenyl   (e.g.,   4H-1, 3-dioxin-2-y1,   4H-1, 3-dioxin-4-y1 1

4H-1, 3-dioxin-5-yl, 4H-1, 3-dioxin -6-yl, 2, 3-dihydro-1 1 4-dioxin-2-yl, 2,3-dihydro-1, 4-dioxin-5-yl) and the like;

fused  non-aromatic  heterocyclic  groups  such  as  dihydroindolyl

5 (e.g., 2,3-dihydro-1H-isoindol-1-yl), dihydroisoindolyl (e.g., 1, 3-dihydro-2H-isoindol-2-yl), dihydrobenzofuranyl (e.g., 2 1 3-dihydro-1-benzofuran-5-yl) 1 dihydrobenzodioxinyl (e.g. 1 2, 3-dihydro-1,4-benzodioxinyl), dihydrobenzodioxepinyl (e.g., 3 1 4-dihydro-2H-1, 5-benzodioxepinyl) , tetrahydrobenzofuranyl (e.g. 1

10    4, 5, 6 1 7-tetrahydro-1-benzofuran-3-yl) 1 chromenyl (e.g., 4H-chromen-2-yl1 2H-chromen-3-yl) 1 dihydroquinolinyl (e.g., 1 1 2-dihydroquinolin-4-yl) 1 tetrahydroquinolinyl (e.g. 1 1 1 2 1 3 1 4-tetrahydroquino1in-4-yl), dihydroisoquino1iny1 (e.g., 1 1 2-

dihydroisoquino1in-4-yl),  tetrahydroisoquinoliny1   (e.g. 1   
15   1, 2 1  3 1  4-tetrahydroisoquino1in-4-yl) ,   dihydrophthalazinyl    (e.g. 1
1, 4-dihydrophthalazin-4-yl),  hexahydropyrazinooxazinyl   (e.g. 1
hexahydropyrazino[2,1-cJ [1,4Joxazinyl)   and  the  like;   
and  the  like  can  be  mentioned.   
The  "heterocyclic  group"  of  the  aforementioned   
20    "optionally  substituted  heterocyclic  group"  optionally  has  1
to  3  su.bstituents  at  su.bsti tutable  positions.   As  such   
substituents 1    those  exemplified  as  the  substituents  which    the
C3-l(}   cycloalkyl  group  and  the  like  exemplified  as  the   

"hydrocarbon  group"  of  the  "optionally  substituted  hydrocarbon

25 group" for R 61 R7 1 R21 or R22 optionally has 1 can be mentioned. As the "C6- 14 aryl group" of the "optionally substituted
C6_ 14 aryl group" for R3 1 those similar to the "C6- 14 aryl group" exemplified as the "hydrocarbon group" of the "optionally substituted hydrocarbon group" for R6 1 R\ R21 or R22 can be

30    mentioned.

The "C6_14 aryl group" optionally has 1 to 3 substituents at substitutable positions. As such substituents, those exemplified as the substituents which the C3- 10 cycloalkyl group and the like exemplified as the "hydrocarbon group,., of the

35    "optionally  substituted  hydrocarbon  group"  for  R6 ,    R7 ,    R21   or  R22


optionally  has,   can  be  mentioned.

R3 is preferably an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group (preferably thienyl, pyridyl, furyl, thiazolyl, imidazolyl) or an

s    optionally substituted C6- 14 aryl group (e.g., phenyl), more preferably an optionally substituted 5- or 6-mernbered monocyclic aromatic heterocyclic group (preferably thienyl, pyridyl, furyl, thiazolyl, imidazolyl), particularly

preferably  a  5-  or  6-mernbered  monocyclic  aromatic  heterocyclic

10 group (preferably thienyl, pyridyl, furyl, thiazolyl, imidazolyl).

As  preferable  specific  examples  for  R3 ,

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group (preferably thienyl, pyridyl, furyl, thiazolyl, imidazolyl)

15    optionally  substituted  by  1  to  3  substituents  selected  from

(a)    a  halogen  atom  {preferably  chlorine  atom),   and

(b)    a  C1- 6   alkyl  group  (preferably  methyl);  and

(2) a C6- 14 aryl group (e.g., phenyl) optionally substituted by 1 to 3 substi tuents selected from

20    (a) a C1 - 6 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably fluorine atom), and

(b)    a  C1_ 6   alkoxy  group  (preferably  methoxy);

can  be  mentioned.

25 R9 , R10 and R11 are each independently a hydrogen atom, a halogen atom, an optionally substituted C1 - 6 alkyl group or an optionally substituted C1- 6 alkoxy group.

The "C1 - 6 alkyl group" of the "optionally substituted C1 - 6 alkyl group" for R9 , R10 or R11 optionally has 1 to 3

30    substituents at substitutable positions. As such substituents, those exemplified as the substituents which the C1 - 10 alkyl group and the like exemplified as the "hydrocarbon group" of

the  "optionally  substituted  hydrocarbon  group"  for  R6 ,    R\   R21

or  R22   optionally  has,  can  be  mentioned.

35    The  "C1- 6   alkoxy  group"  of  the  "optionally  substituted  C1 - 6


alkoxy group" for R9 , R10 or R11 optionally has 1 to 3 substituents at substitutable positions. As such substituents, those exemplified as the substituents which the C1 _10 alkyl group and the like exemplified as the "hydrocarbon group" of

5    the "optionally substituted hydrocarbon group" for R6 , R7 , R21 or R22 optionally has, can be mentioned.

R9 is preferably a hydrogen atom or a halogen atom {preferably chlorine atom) .

10

R10 is preferably a hydrogen atom, a halogen atom, a C1_ 6 alkyl group or an optionally substituted C1 - 6 alkoxy group, more preferably a hydrogen atom, a C1 - 6 alkyl group or an optionally substituted C1- 6 alkoxy group.

15    As  preferable  specific  examples  for  R10 ,

{1)    a  hydrogen  atom;

{2)    a  halogen  atom  (preferably  bromine  atom);

(3)    a  C1- 6   alkyl  group  (preferably  methyl);  and

( 4)   a  c 1 _ 6   alkoxy  group  (preferably  methoxy,   ethoxy,  propoxy,

20    isopropoxy) optionally substituted by 1 to 3 substituents selected from

{a)   a  halogen  atom  (preferably  fluorine  atom),

(b)    a  hydroxy  group,

(c)    a  carboxy  group,

25    (d)   a  carbamoyl  group,

(e)    a  C1 - 6   alkoxy  group  {preferably  methoxy),

{f)    a  C1- 6   alkyl-carbonyl  group   (preferably  acetyl},

{g) a C1 - 6 alkoxy-carbonyl group (preferably ethoxycarbonyl), and

30 (h) a C1_ 6 alkylsulfonyl group (preferably methylsulfonyl); can be mentioned.


R11 is preferably a hydrogen atom, a halogen atom (preferably chlorine atom) or a C1- 6 alkyl group (preferably

35    methyl).


Compound    (I)   does  not  contain

a compound wherein R21 is a hydrogen atom or a C1 - 6 alkoxy-carbonyl group, R22 is a hydrogen atom, and R6 and R1 are both
s    hydrogen  atoms,  and

a compound wherei,n R21 is a hydrogen atom or a C1- 6 alkoxy-carbonyl groug, R22 is a hydrogen atom, and R 6 and R 7 are both methyl groups.


10 Preferable examples of compound (I) is as follow. [Compound (A)]

Compound    (I)   wherein

R1   is  a  hydrogen  atom;

R2   is  a  group  represented  by



A  is  CH  or  N;

R4   and  R5   are  each  independently

(1) a C1 - 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl) optionally substituted
20    by  1  to  3  substituents  selected  from

(a)    a  C1 - 6   alkoxy  group   (preferably  methoxy,  ethoxy),

(b)    a  C1 - 6   alkylsulfonyl  group   (preferably  methylsulfonyl,

ethylsulfonyl),

(c)    a  C1_ 6   alkoxy-carbonyl  group   {preferably  methoxycarbonyl,

25    ethoxycarbonyl),  and

(d)    an  aromatic  heterocyclic  group   (preferably  pyridyl);  or

{2)    a  C3- 10   cycloalkyl  group   (preferably  cyclopropyl);  or

R4 and R5 in combination form a nitrogen-containing non-aromatic heterocycle (the ring should not be morpholine)

30 [preferably a monocyclic nitrogen-containing non-aromatic heterocycle (the ring should not be morpholine) (preferably pyrrolidine, oxopyrrolidine, piperidine, thiomorpholine, 1,1-dioxidothiomorpholine, piperazine, oxopiperazine);

a fused nitrogen-containing non-aromatic heterocycle (preferably tetrahydropyrrolo [3, 4-c] pyrrole-1, 3 (2H, 3aH) -diane, hexahydropyrazino [2, 1-c] [1, 4] oxazin-4 (3H) -one,

hexahydro [1, 3] oxazolo [3, 4-a] pyrazin-3-one,   5, 6, 7, 8-

5    tetrahydro [1, 2, 4] triazolo [ 4, 3-a] pyrazine);  or

a nitrogen-containing spiro heterocycle (preferably 1-oxa-3, 8-diazaspiro[4.5]decan-2-one)] optionally substituted by 1 to 3

substi tuents  selected  from

(1)    a  C1 - 6   alkyl  group  (preferably  methyl,  ethyl,  propyl,

10    isopropyl, butyl, isobutyl, tert-butyl) optionally substituted by 1 to 3 substituents selected from

(a)    a  halogen  atom  (preferably  fluorine  atom),

(b)    a  carboxy  group,

(c)    a  hydroxy  group,

15    (d)   a  C1- 6  alkoxy  group  (preferably  methoxy,   ethoxy),

(e)    a C1- 6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl),

(f)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by

C1_ 6   alkyl  group (s)   (preferably  methyl),   and

20 (g) a non-aromatic heterocyclic group (preferably tetrahydrofuranyl),

(2)    an aromatic heterocyclic group (preferably pyridyl, pyrirnidinyl) optionally substituted by 1 to 3 C1 _ 6 alkyl groups,

(3)    an  amino  group  optionally  mono-  or  di-substituted  by  C1_ 6

25    alkyl-carbonyl  group(s)   (preferably  acetylamino),

(4)    a  C1 - 6   alkyl-carbonyl  group   (preferably  acetyl),

(5)    a C1- 6 alkoxy-carbonyl group (preferably methoxycarbonyl, ethoxycarbonyl),

(6)    a  non-aromatic  heterocyclyl-carbonyl  group  (preferably

30    pyrrolidinylcarbonyl),

(7)    a C1_ 6 alkylsulfonyl group (preferably methylsulfonyl, ethylsulfonyl),

(8)    a  carbamoyl  group,

( 9)   a  hydroxy  group,  and

35    (10)   an  aromatic  heterocyclyl-oxy  group  (preferably

pyrirnidyloxy,    pyrazinyloxy),

W is  NR8 ;

R8   is

(1)    a  hydrogen  atom,

s    (2) a c 1_ 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents

selected  from

(a)    a  C3- 10   cycloalkyl  group   (preferably  cyclopropyl),  and

(b)    a  C1 - 6   alkoxy  group   (preferably  methoxy,   ethoxy);

10 R3 is a 5- or 6-mernbered monocyclic aromatic heterocyclic group (preferably thienyl);

R9 is a hydrogen atom or a halogen atom (preferably chlorine atom) ;

R10   is  a  hydrogen  atom;  and

R11 is a hydrogen atom, halogen atom (preferably chlorine atom) or a C1- 6 alkyl group (preferably methyl).

[Compound    (A1)]

Compound    (A)  wherein  A  is  N.

20

[Compound    (A2) l

Compound    (A)  wherein  A  is  CH.

[Compound    (B)]

25    Compound  (I)  wherein

R1   is  a  hydrogen  atom;

R2   is  a  group  represented  by




30 (1) a C1 - 6 alkyl group (preferably methyl, ethyl, isopropyl) optionally substituted by 1 to 3 substituents selected from
(a)    a  non-aromatic  heterocyclic  group  (preferably

piperidinyl,    pyrrolidinyl,  morpholinyl,  piperazinyl)

optionally  substituted  by  1  to  3  substituents  selected  from

(i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl-carbonyl  group   (preferably  acetyl),

(iii)    a C1- 6 alkylsulfonyl group (preferably methylsulfonyl), and

(iv)    a  halogen  atom  (preferably  fluorine  atom),

(b)    an  amino  group,

(c)    a  hydroxy  group,   and

10    (d)   a  C1 _ 6   alkoxy  group   (preferably  methoxy),

(2)    a  cyano  group,

(3)    a  carboxy  group,

( 4)   a  c1_ 6  alkoxy-carbonyl  group   (preferably  methoxycarbonyl),

(5)    a  carbamoyl  group,  or

15 (6) a non-aromatic heterocyclyl-carbonyl group (preferably pyrrolidinylcarbonyl),

[preferably a C1- 6 alkyl group (preferably methyl, ethyl, isopropyl) substituted by 1 to 3 substituents selected from
(a)    a  non-aromatic  heterocyclic  group   (preferably

20    piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl) optionally substituted by 1 to 3 substi tuents selected from

(i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl-carbonyl  group  (preferably  acetyl),

(iii)    a  C1- 6  alkylsulfonyl  group  (preferably

25    methylsulfonyl),  and

(iv)    a  halogen  atom  (preferably  fluorine  atom) 1,  and

R7   is

(1)    a  hydrogen  atom,   or

(2)    a  C1- 6  alkyl  group   (preferably  methyl);

30 R6 and R7 in combination form a monocyclic non-aromatic heterocycle (preferably piperidine, tetrahydropyran) optionally substituted by 1 to 3 substituents selected from

(a) a C1- 6 alkyl group (preferably methyl, ethyl) optionally substituted by aromatic heterocyclic group (s) (preferably

35    imidazolyl)   optionally  substituted  by  1  to  3  C1 - 6   alkyl
groups    (preferably  methyl),

(b)    a  C7_ 13   aralkyl  group   (preferably  benzyl),

(c)    a  C1 _ 6   alkyl-carbonyl  group   (preferably  acetyl),

(d)    a  C1_ 6   alkylsulfonyl  group   (preferably  methylsulfonyl),

and

(e)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by

C1- 6   alkyl  group(s)   {preferably  methyl);

W  is  NR8;

R8   is

10    (l)   a  hydrogen  atom,

(2)    a c 1 _ 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl) optionally substituted by 1 to 3 substituents

selected  from

(a)    a  C3 - 10   cycloalkyl  group   (preferably  cyclopropyl),   and

15    (b)   a  C1- 6   alkoxy  group  (preferably  methoxy,  ethoxy);

R3 is a 5- or 6-membered monocyclic aromatic heterocyclic group (preferably thienyl};

R9 is a hydrogen atom or a halogen atom (preferably chlorine atom) ;

20    R10   is  a  hydrogen  atom;  and

R11 is a hydrogen atom, halogen atom (preferably chlorine atom) or a C1_ 6 alkyl group (preferably methyl).

[Compound    (C)]

25    Compound  (I)  wherein

R1   is  a  hydrogen  atom  or  a  halogen  atom  (preferably

fluorine  atom);

R2   is  a  group  represented  by




(1) a C1_ 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents


selected  from

(a) a heterocyclic group (preferably piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, l, 1-dioxidothiomorpholinyl, pyrazolinyl, pyrazolidinyl, azetidinyl, imidazolyl, triazolyl) optionally substituted by l to 3 substituents selected from

(i)    a  hydroxy  group,

(ii)    a  C1_ 6   alkyl-carbonyl  group   (preferably  acetyl),

10 (iii) a C1- 6 alkylsulfonyl group (preferably methylsulfonyl),

(iv)    a  halogen  atom  (preferably  fluorine  atom),

(v)    an  oxo  group,

(vi)    a  C1 - 6   alkyl  group  (preferably  methyl,  ethyl)

15    optionally  substituted  by  1  to  3  hydroxy  groups,   and

(vii)    a C1 - 3 alkylenedioxy group (preferably ethylenedioxy),
(b)    an  amino  group  optionally  mono-  or  di-substituted  by

substituent (s)   selected  from

20    (i)   a  C1- 6   alkyl  group  (preferably  methyl,  ethyl,

isobutyl) optionally substituted by l to 3 substituents selected from a hydroxy group and a C1- 6 alkylsulfonyl

group    (preferably  methylsulfonyl),

(ii)    a  C1 - 6   alkyl-carbonyl  group   (preferably  acetyl),

25 (iii) a C1- 6 alkoxy-carbonyl group (preferably methoxycarbonyl) optionally substituted by l to 3 C6- 14 aryl groups (preferably phenyl),

(iv) a C3- 10 cycloalkyl group (preferably cyclohexyl) optionally substituted by 1 to 3 substituents selected

30    from a hydroxy group and a C1 - 6 alkyl group (preferably methyl),

(v)    an aromatic heterocyclic group (preferably triazolyl}, and

(vi)    a  non-aromatic  heterocyclic  group   (preferably

35    tetrahydrothiopyranyl,  1-oxidotetrahydrothiopyranyl,


1, 1-dioxidotetrahydrothiopyranyl),

(c)    a  hydroxy  group,

(d)    a  C1 - 6   alkoxy  group   (preferably  methoxy),

(e)    a C1_ 6 alkylsulfonyloxy group (preferably methylsulfonyloxy),
(f)    a  C1 - 6   alkyl-carbonyl  group   (preferably  acetyl),

(g)    a  C2- 6   alkenyl-carbonyl  group   (preferably  vinylcarbonyl),

(h)    a  c 1_ 6   alkoxy-carbonyl  group   (preferably  ethoxycarbonyl),

(i)    a  carboxy  group,

10 (j) a non-aromatic heterocyclyl-carbonyl group (preferably piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-oxidothiomorpholinylcarbonyl, 1,1-dioxidothiomorpholinylcarbonyl, pyrrolidinylcarbonyl, azetidinylcarbonyl) optionally substituted by 1 to 3 substituents selected from


(i)    a  hydroxy  group,

(ii)    a C1 - 6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 hydroxy groups,

20    (iii)   a  halogen  atom  (preferably  fluorine  atom),   and

(iv)    a  carboxy  group,

(k)    a  non-aromatic  heterocyclyl-carbonyloxy  group

(preferably  morpholinylcarbonyloxy)   optionally  substituted

by  1  to  3  C1_ 6   alkyl  groups   (preferably  methyl),

25    {l) a carbamoyl group optionally mono- or di-substituted by substituent (s) selected from
(i)    a  C1 - 6   alkyl  group  (preferably  methyl,  ethyl)

optionally  substituted  by  1  to  3  substituents  selected

from  a  hydroxy  group,  a  C1- 6   alkoxy  group  (preferably

30    methoxy) and a C1_ 6 alkylsulfonyl group (preferably methylsulfonyl),

(ii)    a  C1- 6   alkoxy  group   (preferably  methoxy),

(iii)    a  C3 - 10   cycloalkyl  group   (preferably  cyclopropyl),

(iv)    a  C1 _6   alkylsulfonyl  group  (preferably

35    methylsulfonyl),

51
 





(v)    an aromatic heterocyclic group (preferably triazolyl, tetrazolyl), and

(vi)    a non-aromatic heterocyclic group (preferably tetrahydropyranyl),

(m)    a  C1_ 6   alkylthio  group  (preferably  methylthio)

optionally  substituted  by  1  to  3  carboxy  groups,   and

(n)    a  formyl  group,

(2)    a  cyano  group,

(3)    a  carboxy  group,

10    (4)   a  C1_ 6   alkoxy-carbonyl  group   (preferably  methoxycarbonyl),

(5) a carbamoyl group optionally mono- or di-substituted by C1 - 6 alkyl group(s) (preferably ethyl), or

(6) a non-aromatic heterocyclyl-carbonyl group {preferably pyrrolidinylcarbonyl, morpholinylcarbonyl,
15    piperazinylcarbonyl) optionally substituted by 1 to 3 C1- 6 alkyl groups (preferably methyl),

[preferably a C1 - 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) substituted by 1 to 3 substituents

selected  from

20 (a) a heterocyclic group (preferably piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1, 1-dioxidothiomorpholinyl, pyrazolinyl, pyrazolidinyl, azetidinyl, imidazolyl, triazolyl) optionally substituted by 1 to 3 substituents

zs    selected  from

(i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl-carbonyl  group  (preferably  acetyl),

(iii)    a C1- 6 alkylsulfonyl group (preferably methylsulfonyl),
30    (iv)   a  halogen  atom  (preferably  fluorine  atom),

(v)    an  oxo  group,

{vi) a C1- 6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 hydroxy groups, and (vii) a C1- 3 alkylenedioxy group {preferably

35    ethylenedioxy)],   and


( 1)   a  hydrogen  atom,  or

(2)    a  c1_ 6   alkyl  group  (preferably  methyl);

R6  and  R7  in  combination  form

s (1) a monocyclic non-aromatic heterocycle (preferably piperidine, tetrahydropyran, 1-oxidotetrahydrothiopyran) optionally substituted by 1 to 3 substituents selected from

(a) a C1 _ 6 alkyl group (preferably methyl, ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

10 (i) an aromatic heterocyclic group (preferably imidazolyl, furyl, pyridyl) optionally substituted by 1 to 3 C1_ 6 alkyl groups (preferably methyl),

(ii)    a  cyano  group,

(iii)    a  hydroxy  group,

15    (iv)   a  carboxy  group,

(v)    a  C1- 6   alkoxy  group   (preferably  methoxy),

(vi)    a  C1 - 6   alkyl-carbonyl  group  (preferably  acetyl),

(vii)    a  C1 _ 6   alkoxy-carbonyl  group   (preferably

methoxycarbonyl),    and

20    (viii) a carbamoyl group optionally mono- or di-substituted by C1 - 6 alkyl group(s) (preferably ethyl),
(b)    a  C 7 _13   aralkyl  group  (preferably  benzyl),

(c)    a  c1_ 6   alkyl-carbonyl  group  (preferably  acetyl),

(d)    a  c1_ 6   alkylsulfonyl  group   (preferably  methylsulfonyl),

25    (e)   a  carbamoyl  group  optionally  mono-  or  di-substituted  by
C    1- 6  alkyl  group (s) (preferably  methyl),  and

(f)    a non-aromatic heterocyclic group (preferably tetrahydropyranyl), or
(2)    a  C3 - 10   cycloalkane   (preferably  cyclohexane)   optionally

30    substituted by 1 to 3 substituents selected from an oxo group and a C1_ 3 alkylenedioxy group (preferably ethylenedioxy);

R21   is

(1)    a  hydrogen  atom,  or

(2)    a  C1- 6   alkyl  group  (preferably  methyl)   optionally

35    substituted  by  1  to  3  substituents  selected  from  a  hydroxy

group and a non-aromatic heterocyclic group (preferably morpholinyl);

R22  is  a  hydrogen  atom;
W is NR8; R8 is

( 1)  a  hydrogen  atom,   or

(2) a C1 - 6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substi tuents selected from

10    (a)   a  C 3- 10   cycloalkyl  group  (preferably  cyclopropyl),

(b)    a  c1_ 6   alkoxy  group   (preferably  methoxy,   ethoxy),

(c)    a  halogen  atom  (preferably  fluorine  atom),

(d)    a  cyano  group,

(e)    a  hydroxy  group,

15    (f)   a  carboxy  group,

(g)    a  carbamoyl  group,  and

(h)    a  C1- 6   alkoxy-carbonyl  group  (preferably

ethoxycarbonyl);

R3  is

20    (1) a 5- or 6-mernbered monocyclic aromatic heterocyclic group (preferably thienyl, pyridyl, furyl, thiazolyl, imidazolyl)
optionally  substituted  by  1  to  3  substituents  selected  from

(a)    a  halogen  atom  (preferably  chlorine  atom),   and

(b)    a  C1_ 6   alkyl  group  (preferably  methyl),   or

25 (2) a C6_ 14 aryl group (e.g., phenyl) optionally substituted by to 3 substituents selected from

(a) a C1 - 6 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atoms (preferably fluorine atom), and

30    (b)   a  C1_ 6   alkoxy  group  (preferably  methoxy);

R9 is a hydrogen atom or a halogen atom (preferably chlorine atom) ;

R 10   is

(1)    a  hydrogen  atom,

35    (2)  a  halogen  atom  (preferably  bromine  atom),


(3)    a  C1 -6   alkyl  group   (preferably  methyl),   or

( 4) a C1 -6 alkoxy group (preferably methoxy, ethoxy, propoxy, isopropoxy) optionally substituted by 1 to 3 substituents selected from

(a)    a  halogen  atom  (preferably  fluorine  atom),

(b)    a  hydroxy  group,

(c)    a  carboxy  group,

(d)    a  carbamoyl  group,

(e)    a  c 1_ 6   alkoxy  group  (preferably  methoxy),

10    (f)   a  C1_ 6   alkyl-carbonyl  group  (preferably  acetyl),

(g)    a  C1_ 6   alkoxy-carbonyl  group   (preferably  ethoxycarbonyl),

and

(h)    a  C1- 6   alkylsulfonyl  group  (preferably  methylsulfonyl);

and

15 R11 is a hydrogen atom, a halogen atom {preferably chlorine atom) or a C1- 6 alkyl group (preferably methyl).

[Compound    {D)]

Compound    {I)  wherein

20 R1 is a hydrogen atom or a halogen atom (preferably fluorine atom) ;

R2   is  a  group  represented  by




25    (1) a C1_ 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents

selected  from

(a)    a  heterocyclic  group   (preferably  piperidinyl,

pyrrolidinyl,    morpholinyl,  piperazinyl,  thiomorpholinyl,   l -

30    oxidothiomorpholinyl, 1, 1-dioxidothiomorpholinyl, pyrazolinyl, pyrazolidinyl, azetidinyl, imidazolyl, triazolyl) optionally substituted by 1 to 3 substituents

selected  from

(i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl-carbonyl  group   (preferably  acetyl),

(iii)    a C1 - 6 alkylsulfonyl group (preferably methylsulfonyl),

(iv)    a  halogen  atom  (preferably  fluorine  atom),

(v)    an  oxo  group,

(vi)    a  C1- 6   alkyl  group   (preferably  methyl,  ethyl)

optionally  substituted  by  1  to  3  hydroxy  groups,   and

10    {vii) a C1 _3 alkylenedioxy group {preferably ethylenedioxy},

(b)    an  amino  group  optionally  mono-  or  di-substituted  by

substituent {s)   selected  from

(i)    a  C1 - 6   alkyl  group   (preferably  methyl,  ethyl,

15    isobutyl) optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1 _ 6 alkylsulfonyl group (preferably methylsulfonyl),

(ii)    a  C1- 6   alkyl-carbonyl  group  {preferably  acetyl},

(iii)    a  C1 - 6   alkoxy-carbonyl  group   (preferably

20    methoxycarbonyl) optionally substituted by 1 to 3 C6- 14 aryl groups (preferably phenyl),
(iv)    a  C3- 10   cycloalkyl  group  (preferably  cyclohexyl)

optionally  substituted  by  1  to  3  substituents  selected

from  a  hydroxy  group  and  a  c 1_ 6   alkyl  group   (preferably

25    methyl),

(v)    an aromatic heterocyclic group (preferably triazolyl} , and

{vi) a non-aromatic heterocyclic group (preferably tetrahydrothiopyrany1, 1-oxidotet rahydrothiopyrany 1,

30    l, 1-dioxidotetrahydrothiopyranyl),

(c)    a  hydroxy  group,

(d)    a  C1 - 6   alkoxy  group   (preferably  methoxy),

(e)    a C1- 6 alkylsulfonyloxy group (preferably methylsulfonyloxy),
35    (f)   a  C1- 6   alkyl-carbonyl  group  (preferably  acetyl),

(g)    a  C2~6 alkenyl-carbonyl  group   (preferably  vinylcarbonyl)

(h) a C1 - 6 alkoxy-carbonyl group (preferably ethoxycarbonyl). ( i) a carboxy group,

(j) a non-aromatic heterocyclyl-carbonyl group (preferably piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-oxidothiomorpholiny1carbony1, 1,1-

di oxidothiomorpholinylcarbony1, pyrrol idin y 1 carbon y 1, azetidinylcarbonyl) optionally substituted by 1 to 3

10    substituents  selected  from

(i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl  group  (preferably  methyl,  ethyl)

optionally substituted by 1 to 3 hydroxy groups, (iii) a halogen atom (preferably fluorine atom), and

15    (iv}   a  carboxy  group,

{k) a non-aromatic heterocyclyl-carbonyloxy group (preferably morpholinylcarbonyloxy) optionally substituted by 1 to 3 C1- 6 alkyl groups (preferably methyl),
(1)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by

20    substituent ( s)   selected  from

(i)    a  C1 - 6   alkyl  group   (preferably  methyl,   ethyl}

optionally  substituted  by  1  to  3  substituents  selected
from  a  hydroxy  group,   a  C1~6 alkoxy  group  (preferably

methoxy}    and  a  C1 - 6   alkylsulfonyl  group  (preferably

25    methylsulfonyl},

(ii)    a  C1- 6  alkoxy  group   (preferably  methoxy),

(iii)    a  C3 - 10   cycloalkyl  group   (preferably  cyclopropyl),

(iv)    a  C1- 6   alkylsulfonyl  group  (preferably

methyl.sulfonyl),

30    (v) an aromatic heterocyclic group (preferably triazolyl, tetrazolyl), and

(vi)    a non-aromatic heterocyclic group (preferably tetrahydropyranyl),

(m)    a  C1- 6   alkylthio  group  (preferably  methylthio)

35    optionally  substituted  by  1  to  3  carboxy  groups,   and

(n)    a  formyl  group,

(2)    a  cyano  group,

( 3)  a  carboxy  group,

(4)    a  C1_ 6   alkoxy-carbonyl  group  (preferably  methoxycarbonyl),

5 (5) a carbamoyl group optionally mono- or di-substituted by C1 - 6 alkyl group (s) (preferably ethyl), or

{6) a non-aromatic heterocyclyl-carbonyl group (preferably pyrrolidinylcarbonyl, morpholinylcarbonyl,
piperazinylcarbonyl)    optionally  substituted  by  1  to  3  C1_ 6  alkyl

10    groups   (preferably  methyl),

[preferably a C1 - 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) substituted by 1 to 3 substituents selected from

(a)    a  heterocyclic  group   (preferably  piperidinyl,

15    pyrrolidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1, 1-dioxidothiomorpholinyl, pyrazolinyl, pyrazolidinyl, azetidinyl, imidazolyl, triazolyl) optionally substituted by 1 to 3 substituents

selected  from

20    (i)   a  hydroxy  group,
{ii)   a  C1 - 6  alkyl-carbonyl  group   (preferably  acetyl),

(iii)    a C1 - 6 alkylsulfonyl group (preferably methylsulfonyl),
(iv)    a  halogen  atom  (preferably  fluorine  atom),

25    (v)   an  oxo  group,

(vi)    a C1 - 6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 hydroxy groups, and
(vii)    a  C1 - 3   alkylenedioxy  group   (preferably

ethylenedioxy) 1,  and

30    R7   is

(1)    a  hydrogen  atom,  or

(2)    a C1- 6 alkyl group (preferably methyl); or R6 and R7 in combination form
(1)    a  monocyclic  non-aromatic  heterocycle   (preferably

35    piperidine,  tetrahydropyran,   1-oxidotetrahydrothiopyran)

optionally  substituted  by  1  to  3  substituents  selected  from

(a) a C 1- 6 alkyl group (preferably methyl, ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

(i)    an  aromatic  heterocyclic  group  (preferably

imidazolyl, furyl, pyridyl) optionally substituted by 1 to 3 C1- 6 alkyl groups (preferably methyl) 1

(ii)    a  cyano  group,

(iii)    a  hydroxy  group,

(iv)    a  carboxy  group,

10    (v)   a  C1 - 6   alkoxy  group   (preferably  methoxy) ,

(vi)    a  C1 - 6   alkyl-carbonyl  group  {preferably  acetyl),

(vii)    a C1- 6 alkoxy-carbonyl group (preferably methoxycarbonyl) 1 and
(viii)    a  carbamoyl  group  optionally  mono-  or  di-

15    substituted  by  C1 - 6   alkyl  group (s)   {preferably  ethyl),

(b)    a  C7- 13   aralkyl  group  (preferably  benzyl),
(c)    a  C1- 6  alkyl-carbonyl  group   (preferably  acetyl),

(d)    a  c1_ 6   alkylsulfonyl  group  (preferably  methylsulfonyl),

(e)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by

20    C1- 6  alkyl  group(s)   (preferably  methyl},  and

(f)    a non-aromatic heterocyclic group (preferably tetrahydropyranyl), or

(2) a C3- 10 cycloalkane (preferably cyclohexane) optionally substituted by 1 to 3 substituents selected from an oxo group
25    and  a  C1 _3   alkylenedioxy  group  (preferably  ethylenedioxy);

W  is  NR9;

R9   is

(1)    a  hydrogen  atom,

(2)    a  C1_ 6   alkyl  group  (preferably  methyl,   ethyl,  propyl,

30    isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

(a)    a  C3- 10   cycloalkyl  group  {preferably  cyclopropyl),

(b)    a  C1_ 6   alkoxy  group  {preferably  methoxy,  ethoxy),

{c)    a  halogen  atom  (preferably  fluorine  atom),

35    (d)   a  cyano  group,

59


(e)    a  hydroxy  group,

(f)    a  carboxy  group,

(g)    a  carbamoyl  group,   and

(h)    a C1_ 6 alkoxy-carbonyl group {preferably ethoxycarbonyl);
R3  is

(1) a 5- or 6-membered monocyclic aromatic heterocyclic group {preferably thienyl, pyridyl, furyl, thiazolyl, imidazolyl) optionally substituted by 1 to 3 substituents selected from

10    (a) a halogen atom (preferably chlorine atom), and {b) a C1_ 6 alkyl group (preferably methyl), or
{2) a C6_ 14 aryl group (e.g., phenyl) optionally substituted by to 3 substituent.s selected from

(a)    a  C1 - 6  alkyl  group  {preferably  methyl)   optionally

15    substituted by 1 to 3 halogen atoms (preferably fluorine atom), and

(b)    a  C1- 6  alkoxy  group   (preferably  methoxy);

R9 is a hydrogen atom or a halogen atom (preferably chlorine atom);

20    R 10   is

(1)    a  hydrogen  atom,

(2)    a  halogen  atom  (preferably  bromine  atom),

(3)    a  C1_ 6   alkyl  group   (preferably  methyl),  or

( 4)   a  C1 _ 6   alkoxy  group   (preferably  methoxy,   ethoxy,  propoxy,

25    isopropoxy) optionally substituted by 1 to 3 substituents selected from

(a)    a  halogen  atom  (preferably  fluorine  atom),

(b)    a  hydroxy  group,

(c)    a  carboxy  group,

30    (d)   a  carbamoyl  group,

(e)    a  C1- 6   alkoxy  group  (preferably  methoxy),

(f)    a  C1 - 6   alkyl-carbonyl  group  (preferably  acetyl),

(g)    a  c1_ 6   alkoxy-carbonyl  group   {preferably  ethoxycarbonyl),

and

35    (h)   a  C1- 6   alkylsulfonyl  group  (preferably  methylsulfonyl);

60


and

R11 is a hydrogen atom, a halogen atom {preferably chlorine atom) or a C1 - 6 alkyl group (preferably methyl) .

s    [Compound  (E)]

Compound    (I)   wherein

R1 is a hydrogen atom or a halogen atom (preferably fluorine atom);

R2   is  a  group  represented  by



10

(1) a C1_ 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) optionally substituted by 1 to 3 substituents selected from

15 (a) a heterocyclic group (preferably piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1, 1-dioxidothiomorpholinyl, pyrazolinyl, pyrazolidinyl, azetidinyl, imidazolyl, triazolyl) optionally substituted by 1 to 3 substituents

20    selected  from

{i)    a  hydroxy  group,

(ii)    a  C1- 6   alkyl-carbonyl  group   (preferably  acetyl),

(iii)    a  C1- 6   alkylsulfonyl  group   (preferably

methylsulfonyl),

25    (iv)   a  halogen  atom  (preferably  fluorine  atom),

(v)    an  oxo  group,

(vi)    a C1- 6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 hydroxy groups, and
(vii)    a  C1 - 3   alkylenedioxy  group   (preferably

30    ethylenedioxy),

(b)    an amino group optionally mono- or di-substituted by substituent (s) selected from



{i} a C1- 6 alkyl group {preferably methyl, ethyl, isobutyl} optionally substituted by 1 to 3 substituents selected from a hydroxy group and a c 1 _ 6 alkylsulfonyl group (preferably methylsulfonyl},

(ii} a C1_ 6 alkyl-carbonyl group (preferably acetyl}, {iii} a C1- 6 alkoxy-carbonyl group (preferably methoxycarbonyl} optionally substituted by 1 to 3 C6- 14 aryl groups (preferably phenyl),

(iv)    a  C3- 10   cycloalkyl  group  (preferably  cyclohexyl}

10    optionally substituted by 1 to 3 substituents selected from a hydroxy group and a C1_ 6 alkyl group {preferably

methyl},

(v} an aromatic heterocyclic group (preferably triazolyl), and

15 (vi) a non-aromatic heterocyclic group (preferably tetr ah ydrothiopyrany1, 1-oxidotetrahydrothiopyrany1, 1, 1-dioxidotetrahydrothiopyranyl),

(c)    a  hydroxy  group,

(d)    a  C1_ 6   alkoxy  group  (preferably  methoxy),

20    (e)   a  C1- 6   alkylsulfonyloxy  group  {preferably

methylsulfonyloxy),

(f)    a  C1_ 6   alkyl-carbonyl  group  (preferably  acetyl),

(g)    a  C2_ 6   alkenyl-carbonyl  group   (preferably  vinylcarbonyl),

(h)    a  C1_ 6   alkoxy-carbonyl  group   (preferably  ethoxycarbonyl),

25    {i)   a  carboxy  group,

(j)    a non-aromatic heterocyclyl-carbonyl group (preferably piperidinylcarbonyl, piperazinylcarbonyl, morpholinylcarbonyl, thiomorpholinylcarbonyl, 1-

oxidothiomorpholinylcarbonyl,    1,1-

30    dioxidothiomorpholinylcarbonyl, pyrrolidinylcarbonyl, azetidinylcarbonyl) optionally substituted by 1 to 3 substituents selected from

(i)    a  hydroxy  group,

(ii)    a  C1_ 6   alkyl  group   (preferably  methyl,  ethyl)

35    optionally  substituted  by  1  to  3  hydroxy  groups,

    a  halogen  atom  (preferably  fluorine  atom),  and

    a  carboxy  group,

(k)    a non-aromatic heterocyclyl-carbonyloxy group (preferably morpholinylcarbonyloxy) optionally substituted
by  1  to  3  c 1_ 6   alkyl  groups   (preferably  methyl),

(1) a carbamoyl group optionally mono- or di-substituted by substituent(s) selected from
(i) a C1 - 6 alkyl group (preferably methyl, ethyl) optionally substituted by 1 to 3 substituents selected

10    from a hydroxy group, a C1- 6 alkoxy group (preferably methoxy) and a C1 - 6 alkylsulfonyl group (preferably methylsulfonyl),

(ii)    a  C1_ 6   alkoxy  group  (preferably  methoxy),

(iii)    a  C3_ 10   cycloalkyl  group  (preferably  cyclopropyl),

15    (iv)   a  C1 _6   alkylsulfonyl  group   (preferably

methylsulfonyl),

(v)    an aromatic heterocyclic group (preferably triazolyl, tetrazolyl), and

(vi)    a  non-aromatic  heterocyclic  group   (preferably

20    tetrahydropyranyl),

(m)    a C1_ 6 alkylthio group (preferably methylthio) optionally substituted by 1 to 3 carboxy groups, and

(n)    a  formyl  group,

(2)    a  cyano  group,

25    (3)   a  carboxy  group,

(4)    a  C1 _ 6   alkoxy-carbonyl  group   (preferably  methoxycarbonyl),

(5)    a  carbamoyl  group  optionally  mono-  or  di-substituted  by  C1- 6

alkyl  group(s)   (preferably  ethyl),   or

(6)    a  non-aromatic  heterocyclyl-carbonyl  group   (preferably

30    pyrrolidinylcarbonyl,  morpholinylcarbonyl,

piperazinylcarbonyl) optionally substituted by 1 to 3 C1 - 6 alkyl groups (preferably methyl),

[preferably a C1 - 6 alkyl group (preferably methyl, ethyl, isopropyl, isobutyl) substituted by 1 to 3 substituents

35    selected  from

(a) a heterocyclic group (preferably piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, thiomorpholinyl, 1-oxidothiomorpholinyl, 1, 1-dioxidothiomorpholinyl, pyrazo1inyl, pyrazolidinyl, azetidinyl, imidazolyl, triazoly1) optionally substituted by 1 to 3 substituents selected from

(i)    a  hydroxy  group,

(ii)    a  C1- 6  alkyl-carbonyl  group  (preferably  acetyl),

(iii)    a  C1 _ 6   alkylsulfonyl  group  (preferably

10    methylsulfonyl),

(iv)    a  halogen  atom  (preferably  fluorine  atom),

(v)    an  oxo  group,

(vi)    a  C1 - 6   alkyl  group   (preferably  methyl,   ethyl)

optionally  substituted  by  1  to  3  hydroxy  groups,   and

15    (vii)   a  C1 - 3  alkylenedioxy  group  (preferably

ethylenedioxy)],    and

R7  is

(1}    a  hydrogen  atom,   or

(2)    a  C1 - 6   alkyl  group   (preferably  methyl);

20    R6   and  R7   in  combination  form

(1)    a monocyclic non-aromatic heterocycle (preferably piperidine, tetrahydropyran, 1-oxidotetrahydrothiopyran)

optionally  substituted  by  1  to  3  substituents  selected  from

(a)    a  C1_ 6  alkyl  group  (preferably  methyl,   ethyl,   isobutyl)

25    optionally  substituted  by  1  to  3  substituents  selected  from

(i)    an  aromatic  heterocyclic  group   (preferably

imidazolyl, furyl, pyridyl) optionally substituted by to 3 C1- 6 alkyl groups {preferably methyl),

(ii)    a  cyano  group,

30    (iii)   a  hydroxy  group,

(iv)    a  carboxy  group,

(v)    a  c 1 _6   alkoxy  group  (preferably  methoxy),

(vi)    a  C1- 6   alkyl-carbonyl  group  (preferably  acetyl),

(vii)    a  C1- 6   alkoxy-carbonyl  group   (preferably

35    methoxycarbonyl),   and


(viii)    a  carbamoyl  group  optionally  mono-  or  di-

substituted  by  C1-6   alkyl  group{s)   (preferably  ethyl},

(b)    a  C7_ 13   aralkyl  group   (preferably  benzyl),

(c)    a  C 1_ 6   alkyl-carbonyl  group  (preferably  acetyl},

{d)    a  C1- 6   alkylsulfonyl  group   (preferably  methylsulfonyl},

(e) a carbamoyl group optionally mono- or di-substituted by c1_ 6 alkyl group (s) (preferably methyl}, and

(f) a non-aromatic heterocyclic group (preferably tetrahydropyranyl), or

10    (2} a C3_ 10 cycloalkane (preferably cyclohexane) optionally substituted by 1 to 3 substituents selected from an oxo group and a C1 - 3 alkylenedioxy group (preferably ethylenedioxy);

R 21   is  a  C 1 _ 6   alkyl  group  {preferably  methyl) optionally

substituted  by  1  to  3  substituents  selected  from  a  hydroxy

15    group and a non-aromatic heterocyclic group (preferably morpholinyl);

R 22   is  a  hydrogen  atom;
W  is  NR8 ;

R8   is

20    { 1}  a  hydrogen  a tom,  or

(2}  a  C1 - 6   alkyl  group   (preferably  methyl,   ethyl,  propyl,

isopropyl, isobutyl} optionally substituted by 1 to 3 substituents selected from

(a)    a  C3- 10   cycloalkyl  group  (preferably  cyclopropyl),

2s    {b)   a  c1 _ 6   alkoxy  group  (preferably  methoxy,  ethoxy},

(c)    a  halogen  atom  (preferably  fluorine  atom},

(d)    a  cyano  group,

(e)    a  hydroxy  group,

(f)    a  carboxy  group,

30    (g)   a  carbamoyl  group,  and

(h)    a C1- 6 alkoxy-carbonyl group (preferably ethoxycarbonyl);
R3   is

(1}    a  5-  or  6-membered  monocyclic  aromatic  heterocyclic  group

35    (preferably  thienyl,  pyridyl,   fury!,   thiazolyl,   imidazolyl)


optionally  substituted  by  1  to  3  substituents  selected  from

(a)    a  halogen  atom  (preferably  chlorine  atom),   and

(b)    a  c1_ 6   alkyl  group   (preferably  methyl),  or

(2)    a  C 6_14   aryl  group   (e.g.,  phenyl)   optionally  substituted  by

5    1  to  3  substituents  selected  from

(a)    a C1 _ 6 alkyl group (preferably methyl) optionally substituted by 1 to 3 halogen atom~ (preferably fluorine atom), and

(b)    a  C1- 6   alkoxy  group   (preferably  methoxy);

10 R9 is a hydrogen atom or a halogen atom (preferably chlorine atom) ;

R 10   is

( 1)   a  hydrogen  atom,

( 2)   a  halogen  atom  (preferably  bromine  atom),

15    {3)   a  C1_ 6   alkyl  group   (preferably  methyl),  or

( 4)   a  C1- 6   alkoxy  group  (preferably  methoxy,   ethoxy,  propoxy,

isopropoxy) optionally substituted by 1 to 3 substituents selected from

(a)    a  halogen  atom  (preferably  fluorine  atom),

20    (b)   a  hydroxy  group,

(c)    a  carboxy  group,

(d)    a  carbamoyl  group,

(e)    a  C1_ 6   alkoxy  group   (preferably  methoxy),

(f)    a  C1_ 6   alkyl-carbonyl  group   (preferably  acetyl),

25    (g) a C1 - 6 alkoxy-carbonyl group (preferably ethoxycarbonyl), and

(h)    a  C1- 6   alkylsulfonyl  group   (preferably  methylsulfonyl);

and

R11   is  a  hydrogen  atom,   a  halogen  atom  (preferably

30    chlorine  atom)   or  a  C1 - 6   alkyl  group   (preferably  methyl) .

[Compound    ( F I ]

N, N-dimethyl-2-{ 4- [ (2-{ 7- [methyl ( 2-thienylsulfonyl) amino] -1H-indol-2-yl} -1, 3-thiazol-5-yl) methyl] piperazin-1-yl} acetamide;

35    N-methyl-N- [2- (8-oxa-1-thia-3-azaspiro [ 4. 5] dec-2-en-2-yl) -1H-

indol-7 -yl] thiophene-2-sulfonamide;

N- [2- [ 4- (hydro:xymethyl} -4, 5-dihydro-1, 3-thiazol-2-yl] -5- ( 2-methoxyethoxy) -lH- indol-7 -yl] -N-methylpyridine-2 -sulfonamide; N-methyl-N- { 2- [5- (morpholinomethyl) -4, 5-dihydro-1, 3-thiazol-2-

5    yl] -lH-indol-7-yl} thiophene-2-sulfonamide;

2- (2- { 7- [methyl (pyridin-2-ylsulfonyl) amino] -1H-indol-2-yl}-4, 5-dihydro-1, 3-thiazol-5-yl) acetamide;
N- (difluoromethyl) -N-{2- [5- (morpholinomethyl) -4, 5-dihydro-1, 3-

thiazol-2-yl] -lH-indol-7 -yl} thiophene-2-sulfonamide;

10    2- {2- [7- [methyl (2-thienylsulfonyl) amino] -5- (trifluoromethoxy)-1H-indol-2-yl] -4, 5-dihydro-1, 3-thiazol-5-yl} acetamide;

N- (5- ( 2-methoxyethoxy) -2-{ 5- [ (1-oxidothiomorpholino}methyl]-4, 5-dihydro-1, 3-thiazol-2-yl} -lH-indol-7-yl} -N-methylpyridine-

2-sulfonamide;

15    2- (2- {7- [methyl (2-thienylsulfonyl} amino] -1H-indol-2-yl} -1-thia-3, B-diazaspiro [ 4. 5] dec-2-en-B-yl} acetamide; or

N- [2-{ 5- [ ( 1, 1-dioxidothiomorpholino)methyl] -4, 5-dihydro-1, 3-thiazol-2-yl }-5- (2-methoxyethoxy) -lH-indol-7-yl] -N-

meth y l pyridine- 2 -sulfonamide;

20    a  salt  thereof.

When compound (I) is in the form of a salt, as such salts, for example, a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a

25    salt with basic or acidic amino acid and the like can be mentioned.

As preferable examples of the salt with inorganic base, alkali metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as calcium salt,

30    magnesium salt and the like; and aluminum salts; ammonium salts and the like can be mentioned.

As preferable examples of the salt with organic base, salts with trimethylamine, triethylamine, pyridine, picoline,

ethanolamine,    diethanolamine,  triethanolamine,

35    dicyclohexylamine,  N,N-dibenzylethylenediamine  and  the  like

can  be  mentioned.

As preferable examples of the salt with inorganic acid, salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like can be mentioned.

As preferable examples of the salt with organic acid, salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like

10    be  mentioned.

As preferable examples of the salt with basic amino acid, salts with arginine, lysine, ornithine and the like can be mentioned.

As  preferable  examples  of  the  salt  with  acidic  amino  acid,

15 salts with aspartic acid, glutamic acid and the like can be mentioned.

A prodrug of the compound (I) means a compound which is converted to the compound (I) with a reaction due to an enzyme, an gastric acid, etc. under the physiological condition in the

20    living body, that is, a compound which is converted to the compound (I) with enzymatic oxidation, reduction, hydrolysis and the like; a compound which is converted to the compound

(I)    by  hydrolysis  and  the  like  due  to  gastric  acid  and  the

like.   A  prodrug  of  the  compound  (I)  may  be  a  compound  obtained

25    by subjecting an amino group in the compound (I) to an acylation, alkylation or phosphorylation (e.g., a compound obtained by subjecting an amino group in the compound (I) to an eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-1, 3-dioxolen-4-yl) methoxycarbonylation,

30 tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation or tert-butylation); a compound obtained by subjecting a hydroxy group in the compound (I) to an acylation, alkylation, phosphorylation or boration (e.g., a compound obtained by subjecting an hydroxy group in the

35    compound   (I)   to  an  acetylation,   palmitoylation,   propanoylation,

pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation); a compound obtained by subjecting a carboxyl group in the compound (I) to an esterification or arnidation (e.g., a compound obtained by

5    subjecting a carboxyl group in the compound (I) to an ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1, 3-dioxolen-4-yl)methyl esterification,

cyclohexyloxycarbonylethyl esterification or methylamidation) and the like. These compounds can be produced from the compound (I) according to a method known per se.

A  prodrug  of  the  compound  (I)  may  also  be  one  which  is

15    converted into the compound (I) under a physiological condition, such as those described in IYAKUHIN NO KAIHATSU (Development of Pharmaceuticals), Vol. 7, Design of Molecules, p.163-198, Published by HIROKAWA SHOTEN (1990).

The  compound   (I)  may  be  labeled  with  an  isotope   (e.g.,  3H,

20    14c,  35 8,  125 I  etc.)   and  the  like.

Furthermore, the compound (I) may be a non-hydrate hydrate.

Deuterium-converted compound wherein 1H has been converted to 2 H(D) are also encompassed in the compound (I).

25 The compound (I) or a prodrug thereof (hereinafter sometimes to be abbreviated as the compound of the present invention) shows low toxicity and can be used as an agent for the prophylaxis or treatment of various diseases to be

mentioned  later  for  mammals   (e.g.,   humans,  mice,   rats,   rabbits,

30    dogs, cats, bovines, horses, pigs, monkeys etc.) as they are or by admixing with a pharmacologically acceptable carrier and

the like to give a pharmaceutical composition. Here, various organic or inorganic carriers

conventionally  used  as  materials  for  pharmaceutical

35    preparations  are  used  as  a  pharmacologically  acceptable

carrier, which are added as excipient, lubricant, binder and disintegrant for solid preparations; or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid preparations, and the like. Where

5    necessary, an additive for pharmaceutical preparations such as preservative, antioxidant, coloring agent, sweetening agent and the like can be used.

Preferable  examples  of  the  excipient  include  lactose,

sucrose,    D-mannitol,  D-sorbitol,   starch,  a-starch,  dextrin,

10    crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxyrnethylcellulose, gum acacia, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, magnesium

aluminate  metasilicate  and  the  like.

Preferred  examples  of  the  lubricant  include  magnesium

15    stearate, calcium stearate, talc, colloidal silica and the like.

Preferable examples of the binder include a-starch, saccharose, gelatin, gum acacia, methylcellulose,

carboxyrnethylcellulose,    sodium  carboxyrnethylcellulose,

20    crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pull ulan, hydroxypropy!cellulose, hydroxypropy lmeth y !cellulose,

polyvinylpyrrolidone  and  the  like.

Preferable examples of the disintegrant include lactose, sucrose, starch, carboxyrnethylcellulose, calcium

25 carboxyrnethylcellulose, sodium croscarrnellose, sodium carboxyrnethylstarch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose and the like.

Preferable examples of the solvent include water for injection, physiological brine, Ringer's solution, alcohol,

30 propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.

Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisarninomethane, cholesterol,

35    triethanolamine,  sodium  carbonate,   sodium  citrate,   sodium


salicylate,    sodium  acetate  and  the  like.

Preferred examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium

5    chloride, benzethonium chloride, glyceryl monostearate and the like; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcell ulose, hydroxyethylcellulose,

hydroxypropylcellulose  and  the  like;  polysorbates,

10 polyoxyethylene hydrogenated castor oil and the like. Preferred examples of the isotonicity agent include

sodium chloride, glycerol, 0-rnannitol, 0-sorbitol, glucose and the like.

Preferred  examples  of  the  buffer  include  buffers  such  as

15 phosphate, acetate, carbonate, citrate and the like. Preferred examples of the soothing agent include benzyl
alcohol  and  the  like.

Preferred examples of the preservative include p-oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol,

20    dehydroacetic  acid,   sorbic  acid  and  the  like.

Preferred examples of the antioxidant include sulfite, ascorbate and the like.

Preferable examples of the coloring agent include water-soluble edible tar pigments (e.g., foodcolors such as Food

25    Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake pigments (e.g., aluminum salt of the aforementioned water-soluble edible tar pigment), natural pigments (e.g., beta

carotene,    chlorophil,   red  iron  oxide)  and  the  like.

30 Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.

The dosage form of the aforementioned pharmaceutical composition is, for example, an oral agent such as tablets

35    (inclusive  of  sugar-coated  tablets,   film-coated  tablets,

sublingual tablets and orally dis integrable tablets), capsules (inclusive of soft capsules and microcapsules), granules, powders, troches, syrups, emulsions, suspensions, films (e.g. orally disintegrable film) and the like; a parenteral agent

5    such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), external agents (e.g.,

transderrnal preparations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal

10 preparations, pulmonary preparations {inhalations), ophthalmic preparations and the like, and the like. These may be administered safely via an oral or parenteral (e.g., topical, rectal, intravenous administrations etc.) route.

These  agents  may  be  controlled-release  preparations  such

15    as rapid-release preparations and sustained-release preparations (e.g., sustained-release microcapsules) .

The  pharmaceutical  composition  can  be  produced  according

to  a  method  conventionally  used  in  the  field  of  pharmaceutical

preparation,    such  as  the  method  described  in  Japan

20    Pharmacopoeia and the like. Concrete production methods of preparations are described in detail in the following.

While  the  content  of  the  compound  of  the  present

invention  in  the  pharmaceutical  composition  varies  depending

on  the  dosage  form,   dose  of  the  compound  of  the  present

25    invention and the like, it is, for example, about 0.1 to 100 wt%.

The  compound  of  the  present  invention  has  a  superior  GK

activating action, and can be used as an agent for the prophylaxis or treatment of various diseases for mammals {e.g.,

30 human, bovine, horse, dog, cat, monkey, mouse, rat, specifically human). In addition, as the compound of the present invention has a selective GK activating action, it shows low toxicity {e.g., acute toxicity, chronic toxicity, cardiotoxicity, carcinogenic, genetic toxicity), which causes

35    fewer  side  effects.

72
 



~CLAIMS

1.   A  compound  represented  by  the  formula   (I) :

R'~R' (I)
.•y~'

RLso;W

s    wherein

R1 is a hydrogen atom or a halogen atom; R2 is a group represented by

or

wherein

10    A  is  CH  or  N;

R4   and  R5   are  each  independently  an  optionally  substituted
C1 - 6 alkyl group or an optionally substituted C3- 10 cycloalkyl group, or R4 and R5 in combination form an optionally
substituted  ring  wherein  the  ring  should  not  be  morpholine;

15    and

R6, R7, R21 and R22 are each independently a hydrogen atom, an optionally substituted hydrocarbon group, a cyano group

or an acyl group, or R6 and R7 in combination form an optionally substituted ring;

20    W is 0 or NR6 wherein R8 is a hydrogen atom, an optionally substituted C1 -6 alkyl group or an optionally substituted C3- 10 cycloalkyl group;

R3   is  an  optionally  substituted  heterocyclic  group  or  an

optionally  substituted  C6- 14   aryl  group;  and

25    R9 , R10 and R11 are each independently a hydrogen atom, a halogen atom, an optionally substituted C1 - 6 alkyl group or an optionally substituted C1-6 alkoxy group,

provided  that

a  compound  wherein  R21   is  a  hydrogen  atom  or  a  C1 _6   alkoxy-
 


carbonyl group, R22 is a hydrogen atom, and R6 and R7 are both hydrogen atoms, and

a compound wherein R21 is a hydrogen atom or a C1- 6 alkoxy-carbonyl grou_E'§', R22 is a hydrogen atom, and R6 and R7 are both methyl groups

are  excluded,

a    salt  thereof.

2.    The  compound  of  claim  1  which  is  a  co!Jlifound  representee  by

10    the  formula   (I):




wherein

R1  is  a  hydrogen  atom  or  a  halogen  atom;
R2  is  a  group  represented  by

or

wherein

A  is  CH  or  N;

R4 and R5 are each independently an optionally substituted C1 - 6 alkyl group or an optionally substituted C3- 10 cycloalkyl

20    group, or R4 and R5 in combination form an optionally substituted ring wherein the ring should not be morpholine;

and

R6  and  R7   are  each  independently  a  hydrogen  atom,   an
optionally  substituted  hydrocarbon  group,   a  cyano  group

25    an  acyl  group,   or  R6  and  R7   in  combination  form  an

optionally  substituted  ring;

W is  0  or  NR8  wherein  R8  is  a  hydrogen  atom  or  an  optionally
substituted  C1 - 6  alkyl  group;
R3  is  an  optionally  substituted  heterocyclic  group;  and
30    R9,  R10   and  R11  are  each  independently  a  hydrogen  atom,  a
 


halogen atom, an optionally substituted C1 _6 alkyl group or an optionally substituted C1- 6 alkoxy group,
provided  that

a compound wherein R6 and R7 both hydrogen atoms, and a compound wherein R6 and R7 both methyl groups

are  excluded,

or  a  salt  thereof.

3.   The  compound  of  claim  1,  wherein  R2   is  a  group  represented

10    by

R~  ••:

~tR':

N

wherein  R6  and  R7  are  as  defined  in  claim  1.

4.   The  compound  of  claim  3,  wherein  R6   is  a  C1 - 6   alkyl  group

15    substituted by an optionally substituted heterocyclic group. 5. The compound of claim 3, wherein R7 is a hydrogen atom.

6.    The  compound  of  claim  3,  wherein  R6  and  R7   in  combination

20    form  an  optionally  substituted  ring.

7. The compound of claim 3, wherein W is NR8 wherein R8 is as defined in claim 1.


25    8. The compound of claim 3, wherein R3 is a 5- or 6-membered monocyclic aromatic heterocyclic group.

9. The compound of claim 3, wherein R9 is a hydrogen atom or a halogen atom.

30

10. The compound of claim 3, wherein R10 is a hydrogen atom, a halogen atom, a C1 - 6 alkyl group or an optionally substituted C1- 6 alkoxy group.
 



11.    The  compound  of  claim  3,  wherein  R11   is  a  hydrogen  atom,   a

halogen  atom  or  a  c 1 _ 6  alkyl  group.

5    12. N,N-dimethyl-2-{ 4- [ (2-{ 7- [methyl (2-~:~!ly~.sulfo~ylJ_~in~ 1H-indol-2-yl} -1, 3-thiazol-5-yl) methyl] ~frazi~~

yl} acetamide;

N-methyl-N- [2- (8-oxa-1-thia-3-azaspiro [4. ~en-2""'lf<l•} :lH-indol-7 -yl] thiophene-2 -sulfonamide;

10    N- [2- [ 4- (hydroxymethyl} -4, 5-dihydro-1, 3-thiazol-2-yl] -5- ( 2-methoxyethoxy) -1H- indol-7 -yl] -N-methylpyridine-2-sulfonamide; N-methyl-N- { 2- [5- {morpholinomethyl} -4, 5-dihydro-1, 3-thiazol-2-yl]-1H-indol-7-yl} thiophene-2-sulfonamide;

2- (2- { 7- [methyl (pyridin-2-ylsulfonyl} amino]-lH-indol-2-yl}-

15    4, 5-dihydro-1, 3-thiazol-5-yl) acetamide;

N- (difluoromethyl) -N- { 2- [5- (morpholinomethyl) -4, 5-dihydro-1, 3-thiazol-2-yl]-1H-indol-7 -yl} thiophene-2-sulfonamide;

2- {2- [7- [methyl ( 2-thienylsulfonyl) amino] -5- (trifluoromethoxy)-1H-indol-2-yl] -4, 5-dihydro-1, 3-thiazol-5-yl} acetamide;

20    N- (5- (2-methoxyethoxy) -2- { 5- [ ( 1-oxidothiomorpholino) methyl]-4, 5-dihydro-1, 3-thiazol-2-yl} -1H-indol-7-yl) -N-methylpyridine-2-sulfonamide;

2- {2- { 7- [methyl ( 2-thienylsulfonyl) amino] -1H-indol-2-yl} -1-

thia-3, 8-diazaspiro [ 4. 5] dec-2-en-8-yl) acetamide;  or

25    N- [2- { 5- [ ( 1, 1-dioxidothiomorpholino) methyl] -4, 5-dihydro-1, 3-thiazol-2-yl} -5- (2-methoxyethoxy) -1H-indol-7-yl] -N-

meth y 1 pyridine- 2- sulfonamide; or a salt thereof.

30    13. N, N-Dimethyl-2- { 4- [ (2- {7- [methyl (2-thienylsulfonyl) amino]-1H-indol-2-yl} -1, 3-thiazol-5-yll methyl] piperazin-1-yl}acetamide or a salt thereof.

14.   N-Methyl-N- [2- ( 8-oxa-1-thia-3-azaspiro [ 4. 5] dec-2-en-2-yl)-

35    1H-indol-7-yl] thiophene-2-sulfonamide  or  a  salt  thereof.
 



15. N- [ 2- [ 4- ( Hydroxymethyl) -4, 5-dihydro-1, 3-thiazol-2-yll -5-(2-methoxyethoxy) -1H-indol-7-yl] -N-methylpyridine-2-sulfonamide or a salt thereof.

16. N-Methyl-N- {2- [5- (morpholinomethyl) -4, 5-dih~o-J:, 3-thiazol-2-yl] -1H-indol-7-yl}thiophene-2-sulfot§nide or a salt thereof.

10    17. 2- (2-{7- [Methyl (pyridin-2-ylsulfonyl) ami~:l!~~d?l-~:-. yl} -4, 5-dihydro-1, 3-thiazol-5-yll acetamide or a scil•t--thereof.

18. N- (Difluoromethyl) -N- { 2- [5- (morpholinomethyl) -4, 5-dihydro-1, 3-thiazol-2-yl] -1H-indol-7-yl} thiophene-2-sulfonamide or a

16    salt  thereof.

19. 2-{2- [7- [Methyl (2-thienylsulfonyl) amino] -5-(trifluoromethoxy) -1H-indol-2-yl] -4, 5-dihydro-1, 3-thiazol-5-

yl}acetamide  or  a  salt  thereof.

20

20. N- ( 5- (2-Methoxyethoxy) -2- { 5- [ ( 1-oxidothiomorpholino)methyl]-4, 5-dihydro-1, 3-thiazol-2-yl} -1H-indol-7-yl) -N-methylpyridine-2-sulfonamide or a salt thereof.

25    21. 2- ( 2- { 7- [Methyl (2-thienylsulfonyl) amino] -1H-indol-2-yl} -1-thia-3, 8-diazaspiro [ 4. 5] dec-2-en-8-yl) acetamide or a salt thereof.

22.    N- [2- { 5- [ ( 1, 1-Dioxidothiomorpholino) methyl] -4, 5-dihydro-

JO    1, 3-thiazol-2-yl} -5- ( 2-methoxyethoxy) -1H-indol-7-yl] -N-

methylpyridine-2-sulfonamide  or  a  salt  thereof.

j H~. A  prodrug  of  the  compound  of  claim  1.

Jsj  H~. A  glucokinase  activator  comprising  the  compound  of  claim
 

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